ABSTRACT
According to the National Academy of Sciences, Engineering and Medicine (NASEM), long COVID is defined as “an infection-associated chronic condition that occurs after SARS-CoV-2 infection and is present for at least 3 months as a continuous, relapsing and remitting, or progressive disease state that affects one or more organ systems”.[1]
Current clinical studies suggest that hyperbaric oxygen therapy (HBOT) may be a safe and potentially effective intervention for people with Long COVID. Although it is among the few treatments demonstrating symptomatic improvement across multiple organ systems, the precise biological mechanisms remain under investigation. Proposed pathways include:
- Modulation of inflammatory responses
- Mobilization of bone marrow–derived stem cells
- Regulation of immune function and mitochondrial activity
- Restoration of microvascular circulation
While these mechanisms are not yet fully confirmed, improvements have been observed in several patient cohorts. Access to HBOT, however, remains limited for many individuals who might benefit. Given the substantial impact of Long COVID on workforce participation and healthcare expenditures, strategies to broaden treatment availability will be an important topic for future discussion.
This topic provides an overview on the use of hyperbaric oxygen therapy (HBOT) for Long COVID, including epidemiology, risk factors, etiology, pathophysiology, history, diagnosis, current treatment alternatives, and current evidence on the use of HBOT for Long COVID. For a discussion on barriers to implementing HBOT as the standard of care for Long COVID, see blog post "Beyond Clinical Evidence: Navigating the Barriers to HBOT in Long COVID Treatment". For other HBOT emerging indications, refer to topics "HBO Treatment Emerging Indications" and blog post "Investigational HBOT Indications".
Background
Definition
- Long COVID, as a new disease, has been plagued by inconsistent terminology developed by governmental agencies, medical societies, journals, and health organizations in the United States (US) and internationally. This has caused confusion among clinicians, has limited research dissemination, and has impeded patients from obtaining recognition, care and support.
- The National Academy of Sciences, Engineering and Medicine (NASEM) defines long COVID as follows [1]:
- “Long COVID is an infection-associated chronic condition that occurs after SARS-CoV-2 infection and is present for at least 3 months as a continuous, relapsing and remitting, or progressive disease state that affects one or more organ systems”
- The Academy recently published a document describing a unifying nomenclature and definition of Long COVID, as well as all the elements of the disease and its consequences. [2]
Relevance
- Long COVID is a challenging clinical entity for a variety of reasons: the number of people affected, the significance of disability, the number of symptoms, the variability in presentation, the difficulty in diagnosis, and the lack of a broadly available effective treatment. Up until recently, the definition and nomenclature could also be included in this list.
- Long term medical consequences: Long COVID has significant long term medical consequences for individuals that are affected. Given the fact that this problem also affects millions if not billions of people worldwide, it has a significant economic and social impact on communities, societies and nations. [3]
- Impact on quality of life: The symptoms of Long COVID may improve somewhat over time but for many, the symptoms are persistent and result in significant disability that can last for years.[4]
- Impact on productivity: A significant number of cases of Long COVID and its associated disabilities affect the working class and result in loss of work force and associated productivity. The direct and indirect costs of the Long COVID condition have been recently estimated to range from $140 to $600 billion in the US annually and 2-3 trillion globally. [5] To put this into perspective of other medical diagnosis that HBO providers treat, the annual economic impact of diabetic foot ulcers (DFU) is US$ 9-13 billion in the US. [6]
- Lack of well-defined treatment protocols: To date, there is not a widely accepted effective treatment for all, or even most, of the symptoms associated with Long COVID. Long COVID can affect every organ system in the human body, resulting in hundreds of symptoms and new disease presentations. This makes not only diagnosis difficult, but the search for an effective overall treatment seems beyond reach. However, if one considers a unifying underlying pathophysiology, a systemic process that can affect any organ system, and the organism globally, then the search for an effective treatment can be more focused. Indeed, most of the current research efforts are aligned with this idea.
Epidemiology
Prevalence
- Long COVID is thought to affect 10-35% of all those that have contracted and recovered from acute SARS-CoV-2 infection.[7]
- By the end of 2022, the SARS-CoV-2 infection had affected 77% of the United States (US) population.[8]
- If 15% of these go on to develop Long COVID then the number of people that have had Long COVID is 35 million people in the US and approaches 1 billion worldwide.[9][10]
- There is an inherent degree of uncertainty in accurately identifying the number of people in the US and worldwide with Long COVID. Regardless, the number is significant. To put this into perspective, the likely number of Long COVID cases in the US (35 million) exceeds the number of adults diagnosed with diabetes (29.4 million).[11]
Incidence
- The incidence of long COVID is declining and recent analysis suggests that approximately 3.5 % of vaccinated people will go on to develop Long COVID. The is thought to be related to the effectiveness of immunizations and through the emergence of virus variants. However, there are still about a million new cases of acute SARS-CoV-2 infection daily in the US. At this rate, the number of Long COVID would increase by 12.4 million new cases per year among those vaccinated and at higher rates among those that are not.[12]
- The incidence of long COVID is estimated at 10–30% of non-hospitalized cases, 50–70% of hospitalized cases and 10–12% of vaccinated cases. [13]
Risk Factors
Anyone who gets COVID-19 can experience Long COVID, including children. [14]
Several risk factors are associated with an increased likelihood of developing Long COVID [13][15]:
- Female sex
- Individuals older than 40 years
- High body mass index (> or = 30)
- Smoking
- Presence of comorbidities
- Previous hospitalization
- Hispanic or Latino heritage
- Lower income and an inability to adequately rest in the early weeks after developing COVID-19
On the other hand, evidence shows that vaccination lowers the risk of Long COVID, even among individuals with other risk factors such as advanced age or elevated body mass index - thereby extending the benefits of vaccination beyond reductions in acute-phase morbidity and mortality.[15]
Etiology
While still under investigation, multiple, potentially overlapping mechanisms have been proposed to explain Long COVID’s varied symptoms. Key hypotheses include [13]:
- Persistent viral reservoirs
- Immune dysregulation: altered immune responses, sometimes accompanied by reactivation of latent pathogens such as Epstein–Barr virus or human herpesvirus 6, could drive ongoing disease.
- Microbiome and virome disturbances: SARS-CoV-2–induced shifts in gut and respiratory microbiota (including resident viruses) may contribute to chronic symptoms.
- Autoimmunity
- Microvascular thrombosis and endothelial dysfunction
- Neuro-autonomic dysregulation: disrupted signaling in the brainstem or along the vagus nerve may underlie fatigue, dysautonomia, and other neurologic features.
Pathophysiology
- The pathophysiology of Long COVID is not yet fully understood but current areas of research include chronic inflammation, dysregulated immune response, vascular injury with macro and micro vascular thrombosis resulting in end organ hypoxia and loss of function, mitochondrial dysfunction, and sequestered virus with an associated ongoing immune response. [16]
- These mechanisms can affect every organ system, potentially accounting for the more than 200 symptoms and clinical presentations associated with Long COVID.[2]
ASSESSMENT
Long COVID can present in a multitude of ways with hundreds of possible individual symptoms and/or diagnosable conditions affecting any organ system.[2]
History
Chief Complaint and History of Present Illness
- Age and other demographics[2]: Long COVID can affect adults and children and does not discriminate among socioeconomic status, age, gender, sexual orientation, race or ethnicity, geographic location, or previous health or disability
- Onset [2]:
- Long COVID can follow asymptomatic, mild or severe initial SARS-Co-2 infection
- Long COVID can be continuous from the initial acute infection, or it can be delayed weeks or months
- Presentation [2]:
- Common symptoms include shortness of breath, cough, persistent fatigue, post-exertional malaise, difficulty concentrating, memory changes, recurring headache, lightheadedness, fast heart rate, sleep disturbances, problems with taste or smell, bloating, constipation and diarrhea
- Long COVID can exacerbate previous health conditions or present as new symptoms or diagnoses (especially those with a chronic inflammatory component such as rheumatoid arthritis, etc)
- Long COVID can range from mild to severe and can resolve over months or persist for years
- Long COVID can impair an individual’s ability to work, attend school, care for a family member or care for themselves. It can have a profound emotional and physical impact on patients, families, and caregivers.
- Common conditions that can be newly diagnosed or if present before SARS-CoV-2 infection, can be made worse, include: interstitial lung disease, hypoxemia, cardiovascular disease and arrhythmias, cognitive impairment, mood disorders, anxiety, migraine, stroke, blood clots, chronic kidney disease, postural orthostatic tachycardia syndrome and other dysautonomia, myalgic encephalomyelitis (i.e. chronic fatigue syndrome), mast cell activation syndrome, fibromyalgia, connective tissue diseases, hyperlipidemia, diabetes, and autoimmune disorders such as lupus, rheumatoid arthritis and Sjogren’s syndrome.
Diagnosis
- Long COVID is diagnosed based on clinical presentation.[2]
TREATMENT
Current management of Long COVID
- To date, there has been a variety of potential treatments of Long COVID, including physical therapy, systemic and topical anti-inflammatory therapy, dietary and behavioral therapy, cognitive therapy, rehabilitation, immune therapy and anti-coagulation therapy. Unfortunately, none of these have proven universally effective and do not adequately address all of the underlying pathophysiology’s of Long COVID or the constellation of symptoms associated with this entity. [13]
- There have been some selective interventions for individual symptoms (e.g., beta blockers for postural orthostatic tachycardia syndrome and corticosteroids for polymyalgia rheumatica–like symptoms) but none have adequately addressed the entirety of the disease or resulted in improvement of the multiple organ system dysfunction seen in Long COVID. [13] The one exception might be HBOT.
HBOT for Long COVID
HBOT is emerging as one of the most promising treatments for Long COVID. The known effects of HBOT make it an intriguing treatment of Long COVID as it can address the likely mechanisms causing the many symptoms of Long COVID.
- For patients with Long COVID, clinicians might consider HBOT to improve symptoms of Long COVID if resources are available.
- Rationale: HBOT may target the underlying pathophysiology of Long COVID by modulating its key mechanisms (see “Etiology” and “Pathophysiology” above). Table 1 illustrates the specific ways in which HBOT can help manage Long COVID.
- Evidence: In 2024, Katz and Wainwright published a literature review from November 2021 to January 2024 of all published scientific articles related to HBOT for Long COVID [17], including 2 randomized clinical trials (RCTs).[18][19] Results from all the studies showed that HBOT for Long COVID significantly improved many Long COVID symptoms and was safe (See Table 2).[17]
- One of the RCTs investigated the effect of HBOT on Long COVID patients (n=73) with persistent neurocognitive and physical symptoms. [19] The HBOT group received 40 sessions of 2.0 ATA of 100% oxygen for 90 minutes, 5 days per week. Results showed statistically significant improvements in cognitive function, attention, executive function, energy levels, sleep quality, depression, somatization, and pain interference compared to the control group. Brain MRI revealed increased perfusion and microstructural changes in specific brain regions. The study suggested that HBOT can induce neuroplasticity and improve symptoms in Long COVID patients. Follow-up analysis at 1 year post-treatment indicated that the results and physiological changes were sustained.[20]
- Risk and benefit: HBOT is not yet an approved UHMS indication for Long COVID, but published studies show it is effective and safe for reversing or improving symptoms across multiple organ systems, with long-lasting results.
- HBOT for Long COVID has been shown to have minimal side effects if administered in a safe facility (ideally a UHMS-accredited center, or one that follows UHMS/NFPA 99 standards).[17] Side effects appear to be similar to those seen with HBOT for other UHMS approved indications. And similar to UHMS-approved indications, treatment requires a time commitment of daily sessions lasting 2 to 2.5 hours.
- Standardizing treatment protocols and data collection (potentially using platforms like cnsvs.com) can help establish the efficacy of HBOT for Long COVID.
- Utilization of resources: Although a growing body of evidence supports HBOT as an effective treatment for Long COVID, several barriers prevent widespread patient access:
- Lack of recognition as an UHMS approved indication and lack of insurance coverage: Long COVID is not currently an approved indication by UHMS or a covered indication by CMS, which makes HBOT inaccessible to many patients with long COVID who could benefit from treatment.
- Out-of-Pocket Costs: without insurance coverage, the cost of HBOT falls to patients.
- Even if HBOT were covered by insurance and approved by UHMS, there are not nearly enough open chambers to treat 35 million people in a meaningful timeframe.
Table 1. Known Physiologic Effects of HBOT and Potential Effects on Long COVID
| Known Physiologic Effects of HBOT and Potential Effects on Long COVID |
Below, the specific ways in which HBOT can help manage Long COVID are outlined in more detail: - Chronic inflammation: HBOT decreases chronic inflammation by decreasing the inflammatory cytokines (i.e. tumor necrosis factor alpha (TNF-a), Interleukin 1 and 6 (IL-1, IL-6)), and increasing the concentration of anti-inflammatory cytokine Interleukin 10 (IL-10). [21]
- Poor organ function related to hypoxia from micro and macro thrombosis: HBOT improves tissue and end organ perfusion by stimulating angiogenesis through stem cell mobilization. Resulting in enhanced nutrient blood flow and function in hypoxic organs and tissue beds. [22]
- Fatigue, exertional intolerance and mitochondrial dysfunction: HBOT improves mitochondrial function and increases ATP production. [23]
- Associated immune dysregulation: HBOT affects dysregulation of the immune system by inducing stem cell release from the bone marrow and reversing the dysregulated T cell activation. Similar effects are seen with B cells. [24]
- Endothelial cell dysfunction: HBOT decreases endothelial cell dysfunction and subsequent macro and micro thrombosis. [25][26]
|
Table 2. Summary of published studies reviewed by Katz and Wainwright in 2024 (published with permission from S. Wainwright.)
| Author / Year | N | Trial Design | Biomarkers / Testing | Scales | Treatment Profile | Results | Outcome |
| Kjellberg et al. [27] | 20 | Randomized double blind placebo | n/a | RAND-36 6MWT | 2.4 ATA 90 min, two 5-min air breaks x 40 sessions | Trial design, no serious adverse events, favorable safety profile | SAFE |
| Robbins et al. [28] | 10 | Case series | NeuroTrax | Chalder fatigue scale | 2.4 ATA 105 min, 3, 5-min air breaks x 10 sessions over 12 days | Improvement in fatigue and cognitive measures | + |
| Leitman et al. [18] | 79 | Randmized controlled | Echocardiogram | n/a | 2.0 ATA 90 min, three 5-min air breaks x 40 sessions | 48% of long COVID patients demonstrated pre-HBOT systolic dysfunction which was significantly improved with | + |
| Lindenmann et al. [29] | 59 | Prospective | n/a | SF-36 VAS | 2.2 ATA 75 min x 10 sessions (no air breaks mentioned) | In as little as 10 HBOTs - statistical improvement in 80% of metrics, safe and feasible tool for LCS | + |
| Zant et al. [30] | 6 | Clinical case report | ImPACT | Modified Borg dyspnea scale | 2.0 ATA 90 min x 15-29 sessions (no air breaks mentioned) | All patients saw improvement in symptoms scores | + |
| Kitala et al. [31] | 31 | Prospective | Pulse oximetry, spirometry | ROM, EQ-5D-5L psychotechnical test | 2.5 ATA 75 min x 15 sessions (no mention of air breaks) | HBOT resulted in significant and lasting improvement in QOL, endurance, strength, spirometry, memory and attention | + |
| Zilberman-Itskovich et al. [19] | 73 | Prospective randomized sham-controlled | Voxel based neuroimaging | SF-36, PSQI, BSI-18 | 2.0 ATA 90 min, three 5-min air breaks x 40 sessions | HBOT improves cerebral blood flow and brain microstructural changes in those areas that are associated with executive function, cognitive and psychiatric symptoms | + |
| Mrakic-Sposta et al. [32] | 5 | Case series | ROS, TAC, (IL-6, IL1β and TNF-α) lipid peroxidation, DNA damage, No metabolites, neopterin, creatinine, uric acid, spirometry | Fatigue scale | 2.4 ATA 90 min (no mention of air break) N=2, 15 sessions N=2, 30 sessions N=1, 50 sessions | Statistically significant effect of HBOT on biomarkers in all subjects. HBOT is a potential treatment for long COVID patients. | + |
| Bhaiyat et al. [33] | 1 | Case report | Perf MRI, Exercise, spirometry | n/a | 2.0 ATA 90 min, three 5-min air breaks x 60 sessions | Improved cognition and cardiopulmonary function | + |
| Kjellberg et al. [34] | n/a | Safety analysis of HOT-LoCO | n/a | RAND-36 6MWT | 2.4 ATA 90 min, two 5-min air breaks x 10 sessions | Trial design, safety assessment and rationale for HBOT and future study | SAFE |
| Kjellberg et al. [35] | 80 | Prospective randomized sham-controlled | Quality of life, symptoms and physical performance | RAND-36 PF and RP | 2.4 ATA 90 min, two 5-min air breaks x 10 sessions | 10 HBOT sessions did not show more short-term benefits than placebo for Long COVID patients, likely due to small RCT sample size, and small number of HBOT sessions | + (similar to placebo) |
Case study
A case study not yet published elsewhere, by Lindsey, et al. highlights the significant individual disability and recovery of neurocognitive function in a 49-year-old male professional with Long COVID.
Background
Mr. L Covidis (alias) was referred to the HBOT center following an 18-month history of persistent symptoms following acute SARS-CoV-2 infection. The symptoms were many but the most pronounced and debilitating was severe neurocognitive dysfunction. This impairment prevented the patient from working full time in the local court system and caused him to stop driving as he could no longer remember which way to turn at a 4-way traffic stop to get to his destination. This was in a small town in which he had lived his entire life. He had tried many other forms of therapy including a variety of supplements and allographic intravenous stem cell therapy without success. The patient was distraught and thought that he may have to live in an assisted living/memory care home for the rest of his life. He had contemplated suicide as an alternative to living with this condition.
Assessment
The patient had a neurocognitive testing completed by an independent third-party before and after his treatments (CNS Vital Signs). [36]
Treatment
The patient was treated with HBOT receiving once daily sessions (M-F) at 2.2 ATA for 90 minutes with no air breaks for a total of 40 sessions.
Outcomes
The patient had a profound neurocognitive deficit at his pretreatment baseline. The patient scored in the 1 percentile of a normal population in 9 out of 12 tested categories. After treatment, the patient improved his scores in all categories and had 8 out of 12 test scores in the normal range and one in the above normal range. Many other associated symptoms of Long COVID including fatigue, muscle and joint pain, sleep quality, depression and anxiety were also improved (see Figures 1 and 2).
The patient was able to return to work full time and resumed driving and other Activities of daily living essential for independent living. In essence, his life returned to normal. Note that the final neurocognitive testing was done at 31 completed sessions, the patient went on to complete a total of 40 sessions but did not return to do another neurocognitive test.
The treating provider noted that he had rarely seen such a rapid, dramatic reversal of symptoms with a single treatment.
Figure 1. Neurocognitive testing of Long COVID patient before HBOT
Figure 2. Neurocognitive testing of Long COVID patient after 31 HBOT sessions.
APPENDIX
Summary of Evidence (SOE)
(back to text)
Systematic reviews
- In 2024, Katz and Wainwright published a literature review that examined all scientific articles related to HBOT for Long COVID that were published between November 2021 and January 2024. Ten published articles, consisting of eight treatment studies and two safety studies, were included in this review. The review examined 284 patients and encompassed prospective randomized clinical trials, prospective case series, case reports, and safety studies. Results from all the studies showed that HBOT for Long COVID significantly improved many Long COVID symptoms and was safe. [17]
Randomized controlled trials (RCTs)
- In 2025 Kjellberg et al. published a a randomized, placebo-controlled, double-blind, RCT that evaluated the effect of 10 sessions of HBOT on the short- and long-term health related quality of life, symptoms and physical performance in Long COVID patients (n=80) compared with placebo. The HBOT group received 10 sessions of HBOT over six weeks. HBOT was delivered as 100% oxygen at 2.4 ATA for 90 min, with two 5-min air breaks, while the sham protocol used medical air at 1.18–1.32 ATA. At 13 weeks, both groups showed improvement, with no significant difference between HBOT and placebo. Authors concluded that 10 HBOT sessions did not show more short-term benefits than placebo for Long COVID patients. The authors recognize that the lack of significant effect of HBOT compared to placebo could be due to the fact that the sample size was too small (ideally it would have 130 patients to be able to confidently observe a significant difference between group). Also, the number of sessions was possibly too small. In previous RCTs that showed statistically significant difference in favor of HBOT, patients received 40 sessions. [35]
- In 2023 Leitman et al. published a sham-control, double-blind RCT that evaluated the effect of HBOT on the cardiac function of post-COVID-19 (long COVID) patients with ongoing symptoms for at least three months after confirmed infection (n=60). Authors found that compared to the sham group, global longitudinal strain (GLS) significantly increased following HBOT (- 17.8 ± 1.1 to - 20.2 ± 1.0, p = 0.0001), with a significant group-by-time interaction (p = 0.041). Authors concluded that post-COVID-19 syndrome patients despite normal ejection fraction often have subclinical left ventricular dysfunction that is characterized by mildly reduced GLS. HBOT promotes left ventricular systolic function recovery in patients suffering from post COVID-19 condition. [18]
- In 2022 Zilberman-Itskovich et al. published a randomized, sham-controlled, double-blind trial in which they investigated the effect of HBOT Long COVID patients (n=73) who had persistent neurocognitive and other physical symptoms for at least three months following confirmed SARS-CoV-2 infection. [19] Patients in the HBOT group received 40 sessions over 5 days per week. Each HBOT session involved 2.0 ATA of 100% oxygen delivered by face mask for 90 minutes, with five-minute air breaks every 20 minutes. The group receiving HBOT showed statistically significant improvements in global cognitive function, attention, and executive function compared to the control group. Additionally, there were statistically significant improvements in energy levels, sleep quality, depression, somatization, and pain interference. Brain MRI revealed increased perfusion and microstructural changes in specific brain regions associated with cognitive and emotional functions. The study suggests that HBOT can induce neuroplasticity and improve symptoms across multiple organ systems in Long COVID patients, potentially due to increased brain perfusion and neuroplasticity. Follow-up analysis at 1 year post-treatment indicated that the results and physiological changes were sustained. [20]
