Background: Long COVID, as defined by the World Health Organization, refers to the persistence or emergence of new symptoms three months after the initial SARS-CoV-2 infection, lasting for a minimum of two months without any other identifiable explanation. An estimated 50 million individuals grapple with the challenges of long COVID, experiencing a diminished health-related quality of life. Affected individuals endure persistent symptoms extending beyond 12 weeks, defying alternative diagnoses. Despite the prevalence, there are currently no effective therapeutic interventions addressing the underlying pathophysiology of long COVID.
Discussion: To explore potential interventions, a thorough literature search spanning from November 2021 to January 2024 was conducted using PubMed and Google Scholar. Articles containing keywords such as “long COVID” and “hyperbaric oxygen” were meticulously reviewed. The collated published studies, encompassing case series and randomized trials, reveal promising outcomes associated with the application of Hyperbaric Oxygen Therapy (HBO). Notably, HBO demonstrated significant improvements in patients grappling with long COVID.
Conclusion: A substantial cohort of individuals contends with the persistent effects of long COVID or post-COVID-19 syndrome, lacking effective treatment options following recovery from the acute infection. Hyperbaric Oxygen Therapy emerges as a safe treatment modality, exhibiting potential benefits for this population. Further research is warranted to delve into HBO as an adjunctive treatment for long COVID.
Introduction: Amidst the persistent global challenge of the COVID epidemic, a considerable number of patients grapple with the aftermath of their acute infection, experiencing what is commonly known as long COVID or post-COVID-19 syndrome (1). It is estimated that approximately 50 million individuals, constituting 10–20% of those initially diagnosed, endure the burdens of long COVID, with a notable impact on their health-related quality of life (2)(3). The World Health Organization characterizes long COVID as the persistence or emergence of new symptoms three months after the initial SARS-CoV-2 infection, lasting for a minimum of two months without any other explanatory factors (4).
Patients afflicted by long COVID manifest a spectrum of persistent symptoms encompassing dyspnea, cough, fatigue, cognitive impairments, anxiety, depression, sleep disturbances, palpitations, postural tachycardia syndrome (POTS), and rashes, extending beyond a 12-week period without alternative diagnostic explanations (4). Residual effects such as decreased exercise capacity, hypoxia, reduced diffusion capacity, restrictive pulmonary physiology, ground-glass opacities, fibrotic changes on imaging, thromboembolic events, hair loss, and renal impairment have been observed post-resolution of the initial COVID infection (1).
This post-COVID syndrome is a globally recognized phenomenon significantly impacting individuals’ quality of life and productivity. Despite its prevalence, there are currently no effective therapeutic interventions targeting the underlying pathophysiology of long COVID. Recent investigations, encompassing case series and randomized trials, highlight the efficacy of Hyperbaric Oxygen Therapy (HBO) in significantly improving various aspects of patients’ health, including global cognitive function, fatigue, attention, executive function, energy levels, sleep patterns, psychiatric symptoms, cardiopulmonary function, endurance, and pain. The findings suggest that HBO is not only beneficial but also a safe approach in the treatment of patients dealing with the lingering effects of long COVID.
Discussion:
Presentation and Pathophysiology of Long COVID: In a comprehensive observational cohort study spanning 38 Michigan hospitals, outcomes for 1,250 patients were assessed, revealing that 32.6% reported persistent symptoms, including dyspnea, cough, and loss of taste/smell. Factors such as age (40–54), gender (female), co-morbidities, and race (Black individuals) were identified by the CDC as increasing the risk of long COVID. The economic implications of long COVID are significant, particularly impacting those in their peak productive years.
The pathophysiology of long COVID remains elusive, exhibiting variations among individuals. Potential contributors include dysregulated T-cell activation, chronic inflammation, oxidative stress, mitochondrial dysfunction, endothelial dysfunction, thrombotic disease, tissue hypoxia, and direct brain invasion by the virus. A prospective study revealed increased levels of activated monocytes and plasmacytoid dendritic cells in individuals with long COVID symptoms, with persistent elevation of type I and type III interferons, suggesting delayed resolution of inflammation. T-cell dysfunction, thyroid dysfunction, and B-cell involvement may contribute to the autoimmunity pathophysiology. Elevated IL-6 levels observed post-COVID infection contribute to inflammation and oxidative stress, creating a state of hyperinflammation.
Potential Treatment Options: Various treatments for long COVID have been explored, including anti-inflammatory agents, specific diets, cognitive-behavioral therapy, rehabilitation, and hyperbaric oxygen therapy (HBO). While no universally effective treatments have been established, targeted approaches addressing symptom categories have shown efficacy. Pharmacological options, such as β-blockers, low-dose naltrexone, and intravenous immunoglobulin, have demonstrated effectiveness in specific symptom management. Non-pharmacological interventions, including cognitive pacing, increased salt intake, compression stockings, and dietary adjustments, have been employed. Promising supplements like coenzyme Q10 and D-ribose have also shown potential benefits.
Mechanism of Action and Rationale for HBO in Long COVID: Hyperbaric Oxygen Therapy (HBO) exerts its effects through increased pressure and elevated partial pressure of oxygen. This induces the Hyperoxic-Hypoxic Paradox, leading to increased production of reactive oxygen and nitrogen species. HBO influences immune-modulatory cytokines, reducing proinflammatory cytokines and elevating anti-inflammatory cytokines. Intermittent fluctuation of oxygen levels induces oxidative stress scavenger transcription factors, enhancing antioxidant enzyme production.
Mitigating dysregulated T-cell activation, chronic inflammation, and oxidative stress, HBO positively impacts mitochondrial function, reducing overall reactive oxygen species levels. HBO’s influence on stem cell mobilization inhibits abnormal activation of T lymphocytes and macrophages, decreasing proinflammatory cytokine secretion. Overall, HBO provides therapeutic benefits in long COVID by enhancing mitochondrial function, reducing inflammation, mobilizing stem cells, improving thrombotic disease, and alleviating hypoxia.
Numerous studies investigating the use of Hyperbaric Oxygen Therapy (HBO) in patients with long COVID syndrome have yielded promising results. A meticulous literature search from November 2021 to January 2024 revealed significant findings.
- A trial involving six long COVID patients treated with HBO demonstrated improvement in all patients, with 5 out of 6 returning to pre-infection levels. Dyspnea symptoms, initially moderate, significantly reduced after 15 to 29 HBO treatments (22).
- A case series of 10 patients treated with HBO reported statistically significant improvements in fatigue, global cognition, executive function, attention, information processing speed, and verbal function, with no adverse effects noted (23).
- Zilberman-Itskovich et al. conducted a randomized, sham-controlled trial with 73 patients receiving HBO treatments for 40 sessions. Significant improvements were observed in global cognitive function, attention, executive function, energy, sleep, psychiatric symptoms, and pain. Brain MRI indicated improved perfusion and microstructural changes, suggesting HBO’s impact on inducing neuroplasticity (24)(25).
- The ongoing Swedish study HOT-LoCO reported an interim safety report, indicating mostly mild adverse events, supporting the safe utilization of HBO in long COVID patients; however, outcome measures are pending (26).
- A randomized, sham-controlled trial on cardiac dysfunction in long COVID patients showed that HBO significantly increased global longitudinal strain (GLS), enhancing left ventricular systolic function recovery (27).
- A trial evaluating oxy-inflammation biomarkers in long COVID subjects treated with HBO demonstrated a reduction in reactive oxygen species (ROS), lipid peroxidation, DNA damage, nitric oxide metabolites, and inflammatory biomarkers, suggesting HBO’s potential to mitigate COVID-19-induced inflammation (28).
- A prospective trial in 2022 treated 31 patients with 15 HBO sessions, reporting significant and sustained improvement in quality of life, endurance, strength, spirometry parameters, and cognitive functions (29).
- A case report of a 55-year-old male undergoing HBO with pre and post-perfusion MRI demonstrated significant improvements in brain perfusion, white matter brain microstructure, and cognitive and cardiopulmonary function (30).
Overall, these studies provide substantial evidence supporting the efficacy and safety of Hyperbaric Oxygen Therapy as a potential treatment for long COVID, addressing a spectrum of symptoms and improving patients’ quality of life.
Conclusion:
Long COVID presents substantial challenges, particularly affecting individuals in their economically productive years. The accumulated evidence from eight published studies underscores the significant positive impact of Hyperbaric Oxygen Therapy (HBO) on patients diagnosed with long COVID. Currently, there are no alternative treatment options demonstrating similar efficacy in symptom improvement.
HBO emerges as a direct and comprehensive approach to addressing the multifaceted pathophysiology of long COVID, targeting chronic inflammation, small vessel injury, disrupted neural pathways, and mitochondrial dysfunction. The studies reviewed consistently highlight HBO’s potential to enhance the lives of those grappling with the lingering effects of long COVID.
Notably, HBO has proven to be a safe intervention for patients with long COVID, further supporting its potential as an adjunctive treatment. The mounting body of evidence advocates for the continued exploration of HBO as a viable and beneficial therapeutic option for individuals suffering from long COVID symptoms.
In conclusion, the current literature strongly suggests that HBO may offer significant benefits to those affected by long COVID, addressing a spectrum of symptoms and potentially improving overall quality of life. Continued research and exploration of HBO as an adjunctive treatment for long COVID are warranted to further validate its efficacy and refine its application in clinical practice.
