Current findings shed light on its pathogenesis and progression—and offer promising protocols to improve patients’ lives.
As the initial impact of the COVID-19 pandemic subsides, health care practitioners are facing its weighty aftermath—long COVID, and its plethora of respiratory, neurologic, cardiovascular and other symptoms that can linger for weeks, months or even years following the initial infection. While researchers scramble for causes and cures, efforts are focusing on managing the condition and mitigating its devastating manifestations. Here’s what we know about long COVID, with promising interventions that may improve patients’ lives.
Collateral damage: the debilitating consequences of long COVID.
Also known as post-acute sequelae of SARS-CoV-2, long COVID is a multisystemic syndrome encompassing a range of often-severe symptoms at least four weeks after infection. It’s not rare: the U.S. Department of Health & Human Services (HHS) estimates that anywhere from 7.7 million to 23 million Americans have developed long COVID at some point during the pandemic, with the Centers for Disease Control and Prevention (CDC) noting that 6 percent of Americans are affected. While those numbers represent a slight decrease from the previous 7.5 percent, over 25 percent of long-COVID patients report limited ability to carry out day-to-day activities, with significant disruptions in their quality of life.1, 2
More than 200 clinical presentations of long COVID have been identified, impacting multiple organ systems. Symptoms vary among individuals, but the most frequently documented include fatigue that interferes with daily life, post-exertional malaise, difficulty breathing, chest pain, heart palpitations, headaches, cognitive impairment, changes in smell or taste, depression or anxiety, joint and muscle pain, gastrointestinal problems and other autonomic dysfunctions.
Numerous adverse outcomes are associated with long COVID, and common new-onset conditions including cardiovascular, thrombotic and cerebrovascular disease, pulmonary conditions and type 2 diabetes. There’s also a clear increased risk of developing myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and dysautonomia, especially postural orthostatic tachycardia syndrome (POTS ). Cases of new onset ME/CFS and dysautonomia are expected to be lifelong, and cardiovascular and respiratory system damage and complications, such as heart failure or decreased lung function, may be irreversible.
As research continues, potential risk factors are emerging. Women are more likely to develop long COVID, and a higher prevalence is reported in certain ethnicities, including people with Hispanic or Latino heritage. Socioeconomic deprivation, smoking, obesity and a range of comorbidities are implicated. Some preexisting conditions—type 2 diabetes, connective tissue disorders, attention deficit hyperactivity disorder, chronic urticaria and allergic rhinitis—appear to increase the risk, although a third of people with long COVID have no identified preexisting conditions.3,4
Ongoing research suggests multiple, potentially overlapping, causes of long COVID, and several hypotheses for its pathogenesis. Some of these include persisting reservoirs of SARS-CoV-2 in tissues, immune dysregulation with or without reactivation of underlying pathogens such as Epstein-Barr virus, mitochondrial disturbances, alterations in gut microbiota, microvascular blood clotting with endothelial dysfunction, disrupted vagus nerve signaling and other factors.5,6 From a naturopathic or functional medicine perspective, individual constitutions, chronic illnesses and lifestyle considerations like stress, diet and sleep are also thought to increase vulnerability and contribute to the development of long COVID.
A new study revealing specific blood biomarkers in people with long COVID has identified several common characteristics: abnormal T cell activity, reactivation of latent viruses including Epstein-Barr and mononucleosis, and lower levels of cortisol—a finding that most definitively separated people with long COVID from those without, and one that would explain the debilitating fatigue associated with the condition.7
Of particular interest is the relationship between long COVID and CFS. Before the syndrome emerged, a variety of viral and bacterial infections were known to cause postinfectious illnesses such as CFS, and dysautonomia—common in long COVID—is linked with other post viral illnesses.8,9
“The fatigue, brain fog, pain and disordered sleep associated with long COVID simply reflect post-viral chronic fatigue syndrome and fibromyalgia,” says Teitelbaum. “These are very old conditions, and it took more than 40 years and hundreds of studies, including eight by me, to help us understand the causes and effective treatment of these conditions. Ignoring this connection means it will likely take another 40 years to even get close to effective treatment. This is a preventable disaster, which could leave about 8 percent of the population—around 20 million Americans—unnecessarily crippled.”
Treating long COVID: promising protocols and practices.
Pharmacological approaches are limited: there are currently no medications for the condition itself, and drug therapies are purely symptomatic. Functional medicine and integrative strategies offer a far wider range of alternatives. Some proven and promising approaches to incorporate into a personalized protocol.
Easing fatigue: the SHINE protocol.
Originally designed to treat chronic fatigue syndrome and post-viral CFS, the SHINE protocol is an effective therapy for the unremitting fatigue and other complaints associated with long COVID. Developed by Jacob Teitelbaum, MD, long-COVID and CFS researcher, and author of From Fatigued To Fantastic (Avery, 2007), SHINE focuses on restoring energy production and reversing the effects of the hypothalamic and immune dysfunction. The acronym is derived from its multi-pronged approach: optimizing sleep (S), hormone regulation (H), immunity rebuilding (I) and nutritional support (N) and exercise (E)—but only in small amounts that can comfortably be performed to maintain conditioning, since excessive exercise may severely flare the illness.
“These reverse the core issues so the body can reclaim homeostasis and then heal on its own,” Teitelbaum says. A randomized, double-blind, placebo-controlled study of the SHINE protocol found that 90 percent of patients improved, with an average 91 percent increase in quality of life.10 After two years of treatment, most people were able to wean off most of the treatments, while continuing to improve. “It’s a valuable protocol that people can use to facilitate their own healing,” he says.
Listen to the OneMedicinePodcast with Jacob Teitelbaum, MD:
CBD: the role of cannabinoids
The anti-inflammatory and immunomodulating actions of cannabidiol (CBD) are well- documented, and newer research hints at its potential for treating both the acute phases of COVID-19 infection and the lingering effects of long-COVID.
Studies on COVID-19 inflammatory symptoms suggest CBD can inhibit the production of proinflammatory cytokines and reduce inflammatory response, and in one study, treating COVID-19 patients with 300 mg CBD prevented the development of severe infection and decreased chances of hospitalization. Additionally, CBD has been shown to inhibit SARS-CoV-2 spike protein expression in host cells even two hours after infection, effectively eradicating viral RNA expression.
“There is in silico evidence that cannabinoids block spike protein binding of extracellular membranes as well as displacement of spike protein fragments off of cell membrane binding sites,” says Shawn Meirovici, ND. “Furthermore, there are good in vitro and in vivo studies demonstrating a marked anti-inflammatory action of many cannabinoids. I believe cannabinoids, in particular CBD, can play a role in COVID-19 prevention, resolution and treatment, as part of a comprehensive multidisciplinary protocol.”
Preclinical observations demonstrate CBD’s positive effects on immune system dysregulation, inflammation and long-COVID symptoms. A recent feasibility trial found CBD was safe and well tolerated. And because CBD easily crosses the intact blood-brain barrier and can downregulate neuroinflammation, it may greatly benefit the numerous neurological or psychiatric complaints commonly reported in long COVID.11,12,13,14,15
Resolving gut dysbiosis.
A growing body of evidence implicates gut microbiota disruptions in the development and prolongation of long-COVID symptoms. Several studies demonstrate reduced bacterial diversity in COVID-19 patients, along with an abundance of opportunistic and inflammation-related pathogens, and dysbiosis is involved in the pathogenesis of lung injury, anxiety, fatigue, cognitive impairment, depression and other psychiatric symptoms common after infection.16
Therapeutic interventions aimed at restoring the gut microbiome show promise for dampening inflammation, enhancing immune response and alleviating neuropsychiatric manifestations associated with long COVID via the gut-brain axis. Diet and nutrition—including increased dietary fiber and the inclusion of fermented foods and prebiotics—are critical. In addition, probiotic supplements may not only improve COVID-19 symptoms, but also lessen the risk of long-COVID complications, and one recent trial found that a combination probiotic and prebiotic formula helped relieve fatigue, memory impairment and other neuropsychiatric and digestive complaints.17,18,19,20,21
The vagus nerve connection.
Preliminary evidence points to a potential link between long COVID and the vagus nerve, and some studies suggest many troubling symptoms—including shortness of breath, gastrointestinal disturbances and neurocognitive complications—could result from damage to the vagus nerve.22
Also known as cranial nerve X, the vagus nerve touches nearly every organ in the body. Vagus nerve problems disrupt an array of physiological function and may influence common post-COVID manifestations. Impaired vagal activity has been observed in long-COVID patients, and vagus nerve inflammation—frequently seen in COVID-19 patients—is thought to contribute to long-COVID dysautonomia. Vagus nerve neuropathy has also been reported in several studies, and might explain the sore throat, excessive mucus, throat clearing and chronic cough characteristic in long COVID.23,24,25,26
A recent pilot study found that symptoms linked to vagus nerve dysfunction—such as shortness of breath, dizziness, tachycardia, difficulty swallowing, gastrointestinal disturbances and neurocognitive complications—were significantly more prevalent in subjects with long COVID, compared to those who were never exposed to the virus or had fully recovered from infection with no lasting symptoms. Long-COVID subjects were more likely to show thickening of the vagus nerve—presumably a sign of inflammatory damage—and other structural changes to the nerve. Subjects with long-COVID also showed flattened diaphragmatic curve, as well as reduced esophageal peristalsis, increased gastroesophageal reflux. Flattening of the diaphragm and decreased maximum inspiratory pressure could explain such complaints as shortness of breath, difficulty breathing and fatigue. Since lung imaging was normal, researchers suggested respiratory symptoms of long COVID might be caused by damage to the vagus nerve, rather than injury to the lungs.27
These and other findings offer valuable clues for treating long COVID through therapies directed toward the vagus nerve. A variety of approaches, ranging from lifestyle and nutrition interventions to supplement regimens, have been shown to support vagal nerve function. Additionally, non-invasive devices designed to regulate vagus nerve activity may prove to be effective for inflammation, fatigue and other long-COVID manifestations.
One study of patients hospitalized for COVID-19 found that non-invasive vagus nerve stimulation significantly lower levels of inflammatory markers, with the potential to mitigate post-COVID complaints. A small pilot trial suggested transcutaneous auricular vagus nerve stimulation may have a mild to moderate effect in reducing mental fatigue and other long-COVID symptoms, and treatment was safe and well-tolerated. Earlier research also shows demonstrates the benefits of non-invasive brain stimulation, including transcutaneous vagus nerve stimulation, on alleviating fatigue.28,29,30
Traditional Chinese Medicine perspectives.
A number of clinical trials highlight the efficacy and safety of Traditional Chinese Medicine (TCM) in treating the acute stages of COVID-19, and some research suggests TCM may also relieve symptoms of long COVID. Earlier studies showed Chinese medicine combined with conventional treatment was more effective for chronic fatigue syndrome than conventional treatment alone. Other research demonstrates the anti-inflammatory, immunomodulatory and antimicrobial activities of certain Chinese herbs, and specific anti-viral formulations like Myrolea-B, Ilex 15 and Isatis 6 can prevent recurring viral infections in long-COVID patients with vulnerable immune systems.31,32,33,34
“I use some of these herbs regularly,” says Edythe Vickers, ND, LAc, clinical director of An Hao Natural Health Care Clinic in Portland, OR. “Ilex 15, for example, is based on ancient formulas for treating colds and influenza. Patients with long COVID are very susceptible to all the colds and viruses around them, so if they feel an uptick in a sore throat, or a chill or headache, I have them start this formula to stop yet another viral attack.”
In addition to herbal remedies, acupuncture may be a valuable intervention. Research illustrates the efficacy of acupuncture in treating inflammation, autonomic dysfunction, chronic pain, headaches, mood disturbances and chronic respiratory illnesses—symptoms characteristics of long COVID. Several studies also suggest acupuncture may improve palpitations, dyspnea, cognitive impairment, anxiety, depression and other long COVID complaints.35,36,37,38,39 “We use body acupuncture, scalp acupuncture, moxibustion and cupping, individualized for each person,” says Vickers, “and I almost always do ear acupuncture to calm the nervous system and help the body switch into parasympathetic dominance.”
Herbs and supplements: targeting immunity, inflammation, fatigue.
Research hints at vitamins, herbs and supplements as safe, effective options for enhancing immunity, decreasing inflammation and treating the often-debilitating manifestations of long COVID.40 What the evidence suggests:
- Research suggests potential benefits of ginseng in treating CFS, and a recent study showed that a hydroponic form of red ginseng root, containing high levels of noble ginsenosides dramatically improved post-viral CFS and fibromyalgia.41,42
- One small study found 150 mg Pycnogenol daily, in 3 doses of 50 mg, lessened fatigue, oxidative stress, microcirculation and endothelial function after three months, with significant increases in mood and quality of life.43
- A small study of 40 elderly patients experiencing new cognitive decline after SARS-CoV-2 infection showed a nootropic supplement containing bacopa, theanine, saffron, copper and vitamins improved functional status, psychological complaints and depression.44
- Multivitamin and mineral supplements. An observational study of 201 subjects who took a supplement containing vitamins, minerals, amino acids and plant extracts for 28 days found a significant reduction in chronic fatigue and an improvement in health status and quality of life.45
- Omega-3 fatty acids. Omega-3s, especially EPA, benefit mood and neurocognitive disorders by reducing pro-inflammatory cytokines and other mechanisms and supplementing with omega-3s may counteract the negative effects of long COVID on the brain, behavior, and immunity.46
- In one small study of 12 people experiencing at least one long-COVID symptom, creatine for three months significantly reduced fatigue; after six months, participants reported improvements in body aches, breathing issues, loss of taste, headaches and difficulty concentrating compared with placebo.47
- Vitamin C and L-arginine. In a randomized controlled trial of 46 patients with long COVID, a combination of L-arginine and vitamin C supplementation improved fatigue and endothelial dysfunction after 28 days compared with placebo. Another survey suggested a combination of L-arginine (to support endothelial function) and vitamin C (to reduce oxidation) had beneficial effects on long-COVID symptoms.48,49
- Vitamin D. Studies link low blood levels of vitamin D with increased risk of long COVID, highlighting the role of vitamin D supplementation both as a preventive strategy and therapeutic approach to long COVID.50,51
- Elevated inflammation is associated with negative COVID-19 outcomes and a higher risk of developing long COVID. Curcumin has been shown to inhibit severe inflammation and cytokine storm in COVID‐19 infection and can mitigate the persistent inflammation characteristic of long COVID.52,53
It’s not yet known whether long COVID is a syndrome that will resolve over time, or a chronic condition that must be managed indefinitely. With appropriate treatment, including diet and lifestyle interventions that support the body and stop the cycle of inflammation, it’s possible that patients may fully recover. In the meantime, experts agree self-care is key. Plenty of rest, little or no exercise and meditation or breath work to help calm the autonomic nervous system are vital. “We customize treatments to encourage recovery from the inside out,” says Vickers. “I think it all comes down to sleep quality, stress reduction, healthy digestion and finding joy.”
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