“POST-COVID SYNDROME” – A PRE-TRIAL PROPOSITION FOR THE USE OF HYPERBARIC OXYGEN AS A PREVENTION AND CURE FOR CHRONIC POST-COVID SYMPTOMS

An online survey of 151 medical professionals who fell ill in March [1] found 68 are still unable to work. A further 26 went back, only to stop again when symptoms returned. This is 62% of those surveyed.

It appears Covid 19 may be a chronic condition. How long it persists for is unknown. The symptoms can be serious and wide-ranging, affecting the lungs, heart, brain, kidneys, stomach and nervous system. Headaches, shortness of breath, sore throat and feeling exhausted are common. So is recovery followed by frequent relapses.

In this proposal we look at all the possible causes for long term illness after Covid 19 infection – as well as suggesting a therapy that has efficacy across all aetiologies.

Patient comments:

Jo Platt, 46, former Labour MP for Leigh

“This is week 10. I get back pain, like an inflammation. It’s not as severe as it’s been. I have a really strange sensation in my legs, as if I’ve been hill walking. I wake up with sore joints in my fingers. I’ve had gastrointestinal issues and acid reflux. For me the scary thing is the shortness of breath. We still don’t know how long this goes on for and that’s the frightening bit.”

Ginevra Read, 42, psychiatrist, Bristol

“It was very frightening to feel so unwell. Going into week nine I was exhausted. Staying in bed really helped with fatigue but in week 11, I still have low grade fevers, chills, malaise and odd neurological symptoms. I am resting a lot but my improvements have plateaued.

We don’t know what is causing prolonged Covid. Is it the ongoing initial illness, or is it an inflammatory reaction or is it a post-viral syndrome? We don’t know what the prognosis is or what the long-term consequences are. I wonder how many people are having prolonged illness and what the impact is on the workforce, for example. It’s scary to have an illness for which there isn’t any treatment and that doesn’t seem to be going away.”

Iulia Hammond, 39, junior doctor in Manchester

“Every day I am still short of breath. In week six I got a left-sided stabbing chest pain. I now have an abnormal heart rate. This is something you can get with viruses and I’m hoping it will go. You wonder why is this happening? As a physician I have been reading articles. We are learning about coronavirus in real time. The virus is completely novel.

I’m now on day 74 and not at work. Essentially I go bed, kitchen, sofa. There are weeks when I feel I have ridden the wave, and others where I’m back in the wave. I would like to get back to normal life sooner rather than later. It feels very endless.” [2]

This is a mixed picture of symptoms with probably more than one underlying cause. We can project some aetiology from previous coronavirus infections, e.g. SARS and MERS, however there could be other pathologies as Covid 19 has already shown that it works differently to those earlier viruses.

A Post-Viral Picture

A 2011 study from Toronto looking at long term symptomatology after the 2002 SARS [another coronavirus] outbreak found “ Chronic post-SARS is characterized by persistent fatigue, diffuse myalgia, weakness, depression, and non-restorative sleep with associated REM-related apneas/hypopneas “[3]. A Hong Kong study into post-SARS found “The results demonstrated that the rates of psychiatric morbidities, chronic fatigue, and resultant functional disabilities were persistently high and clinically significant. The persistence of psychiatric morbidities among the SARS survivors who participated in our study was alarming. Reviewing the results from previous post-SARS cohorts, the psychiatric morbidities measured by standardized questionnaires ranged from 10% to 35% in the acute phase of the infection (acute phase to 1 month after SARS) to 64% at the 1-year follow-up.  Psychiatric morbidities and chronic fatigue persisted and continued to be clinically significant among the survivors at the 4-year follow-up.” [4]

This is backed up by the ME Association re the current Covid pandemic. Dr C Shepherd quotes:

We are starting to receive reports about previously healthy people who have had  coronavirus infection and have not been able to return to their normal level of health and energy levels in the weeks following the onset of symptoms. These reports are largely from people who have managed at home and not had a more serious infection that required hospital admission. Some reports are from health professionals. It seems likely that some of them are experiencing what is called post viral fatigue (PVF), or a post viral fatigue syndrome (PVFS). We are also receiving reports from people with ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) who have had this infection and now have a significant exacerbation of their ME/CFS symptoms – especially a further reduction in energy levels. “[5]

Lung Damage

Previous Chinese SARS studies have demonstrated that the recovered patients with coronavirus pneumonia can be left with damaged lungs. Impaired lung function was common and could last for months or even years. In the follow-up studies lasting from half a year to two years in the rehabilitating SARS patients, impaired DLCO* was the most common abnormality, ranging from 15.5% to 43.6%.[6]

Classic symptoms are shortness of breath, persistent cough, fatigue and arthralgia/myalgia.

[*DLCO is a test of the diffusing capacity of the lungs for carbon monoxide and is one of the most clinically valuable tests of lung function. The DLCO measures the ability of the lungs to transfer gas from inhaled air to the red blood cells in pulmonary capillaries.]

Abnormal pulmonary function has also been seen after Covid 19 discharge in China – notably a persistent “ground glass” opacity. One study showed 94% of patients still had residual lung disease on final CT before discharge.[21,22]

In the SARS cases, and with Covid 19 the cause is Pulmonary Fibrosis [PF] as a consequence of Acute Respiratory Distress Syndrome [ARDS]. Studies also show the role of inflammatory cytokines, such as IL6 in the pathogenesis of PF. [24]

Pulmonary fibrosis is a pulmonary disease with progressive fibrosis, which is the main factor leading to pulmonary dysfunction and quality of life decline in SARS survivors after recovery. Extensive epidemiological, viral immunological, and current clinical evidences support the possibility that pulmonary fibrosis may be one of the major complications in COVID-19 patients.

ARDS causes diffuse alveolar damage in the lung. There is hyaline membrane formation in the alveoli in the acute stage, and this is followed by interstitial widening and by oedema and then fibroblast proliferation in the organizing stage. COVID-19-ARDS causes the typical ARDS pathological changes of diffuse alveolar damage in the lung. As patients move through the course of their illness, the longer term outcomes of ARDS are starting to be reported, with pulmonary fibrosis appearing as part of COVID-19 ARDS. One study reported that 17% of patients had fibrous stripes in chest CT scans and considered that the fibrous lesions may form during the healing of pulmonary chronic inflammation or proliferative diseases, with gradual replacement of cellular components by scar tissues.[7,8]

 

From the above data, we can see that Covid 19 survivors who suffer the long term debilitating sequelae of this virus can fall into either category, or both.

  • Lung damage from PF/ARDS
  • A “post-viral syndrome”

The former is part of a cytokine mediated inflammatory process, the latter a common problem after a severe viral infection. However from the descriptions given by Post-Covid sufferers, not all can be explained by PF [shortness of breath] and a PVS [fatigue, myalgia, insomnia, mental health issues]

There seems to be another set of symptoms – cardiac, abdominal, illness cyclicality and neurological that could have another cause.

This could be rooted in a rarely seen clinical manifestation of viral pneumonia – but for some reason much commoner with Covid 19 – “Silent Hypoxia”

Silent Hypoxia

“Standing in her patient’s living room, Dr Seim was perplexed. The man, in his 60s, had fallen ill with flu-like symptoms more than a week before. His breathing rate had climbed, so his daughter called the Taarnaasen Medical Centre, the clinic where Seim works as a general practitioner, just outside Oslo, Norway. With COVID-19 at the forefront of her mind, Seim set out to check on the man, and she wasn’t prepared for what she found.“He was sitting in a chair, and he was smiling,” she says. “He didn’t seem bothered in any way.”Yet his breaths came in rapid succession, nearly triple the normal rate. A faint blue tinted his lips and fingers. She truly didn’t grasp how sick he was until she measured the oxygen levels in his blood. A normal percentage would sit well above 90. The number Seim saw was 66. For a split second, Seim thought she had the device turned upside down. “[10]

 

Dr A Rizzo, CMO of the American Lung Association quotes:

“ As with a lot of things regarding COVID-19, we are going to rely on more and more data and studies that show how many individuals develop silent hypoxia. There are probably many COVID-19 patients with hypoxemia who get missed because they are admitted and diagnosed for other reasons such as fever, cough, or other things of that nature. I think we are going to need to look at a larger group of individuals to figure out why exactly the virus causes silent hypoxia, compared to other viruses like influenza, where it is not seen as often. There is something different about this virus in the way that it affects the blood vessels and the airways. There are even some ideas that the virus is affecting the nervous system and affecting the actual mechanisms in our brain that help to regulate respiration. The mechanism of why oxygen levels drop has to do with how well the blood flow through the lungs matches the airflow through the lungs. For some reason, which we cannot identify yet, in certain patients the virus affects both the blood vessels in the lungs, as well as air sacs in the lungs, mismatching the flow of blood and air, causing the oxygen levels to drop. The reason that individuals are not feeling as short of breath or looking to be short of breath is still a bit of a mystery. As with a lot of things to do with COVID-19, this has not been determined yet.   “ [11]

Since the start of the pandemic UK advice has been to self-isolate at home for 14 days if you suspect you have Covid.

Any patient that attends a hospital with suspected Covid would be antigen tested as well as have oximetry to check the Sa02 – if low, they would be admitted and treated with 02 – so these hospital attending silent hypoxia cases would be picked up and treated.

However “home-based” Covid cases do not have Sa02 measured and can suffer silent hypoxia for a long period of time. [9] This clearly will cause highly oxygen dependent organs, e.g. liver, brain/CNS, heart and eyes- severe damage.

There are no research papers currently available about the prevalence/age distribution/mortality and morbidity of silent hypoxia in Covid 19 – especially in the home setting when self-isolating. But the problem is serious enough to warrant home oximeter distribution by motorcycle in one part of London.[28][29]

Likewise, this disease is too young to draw on long term studies as to the effects of silent hypoxia in those that survive Covid 19.

But is there an analogous illness that could give a window to the later effects of this silent hypoxia that also could explain the “post covid syndrome” symptoms not covered by pulmonary fibrosis and post viral syndrome?

Delayed Neuropsychiatric Syndrome [DNS] of Carbon Monoxide Poisoning [COP]

The damage done in COP is due to the hypoxia caused by CO’s binding to the haemoglobin in preference to O2.[15]

In patients who are chronically exposed to low dose of CO, headache, lassitude, thought disorders, dizziness, paresthesia, chest pain, palpitation, visual impairment, nausea, diarrhea, and abdominal pain may be noticed.[30]

It has also been suggested that Covid 19 directly attacks the 1-beta chain of haemoglobin to dissociate the iron to form  porphyrin. The attack will cause less and less haemoglobin that can carry oxygen. [12] So a hypoxaemia exists in both conditions.

[There is no evidence to suggest that CO is the causative factor for DNS in COP – as the severity and timing of DNS is unrelated to COHb level or the duration of COP[15]]

DNS is a recurrent–transient neuropsychiatric consequence of the hypoxia of CO intoxication.

 It manifests with alternating periods of exacerbation and remission that causes diffuse white matter or gray matter injury.

DNS includes a broad spectrum of symptoms. These may vary from mild to severe headache, seizures, alteration in consciousness, lethargy, concentration problems, cognitive disturbances, emotional lability, personality changes, amnesic syndromes, dementia, psychosis, gait disturbances, movement disorders (e.g., parkinsonism), chorea, apraxia, agnosia, inaction, peripheral neuropathy, urinary incontinence, and even vegetative state. [13]

After resolution of symptoms of acute COP, delayed neuropsychiatric syndrome manifests in nearly 20% of patients. Its onset is from 4 to 40 days after COP and the syndrome has a cyclical nature with periods of symptoms alternating with a feeling of wellness. [15]

We suggest that the home-based self-isolators could fall into 1 of 3 groups:

  1. Normal lung function – no sign of silent hypoxia –Sa02 remains normal.
  2. Silent hypoxia in extremis – Sa02 below 75% -these cases will eventually be hospitalized or die at home.
  3. Silent hypoxia moderate – 75% to 95% - these cases would run the hypoxia over a long period, with low enough sats to cause organ damage and mimicking chronic low dose COP with a 20% conversion to DNS later.

Treatment with HBOT

With 3 different potential causes for the symptoms seen in Post-Covid Syndrome [PCS] a standard “one-size fits all” treatment would be the gold standard.

It could be argued that the PVS type could appear in any case of Covid; the pulmonary fibrosis in those who had a cytokine storm or were on ventilation/CPAP support ; and the silent hypoxia cases from the home-based self-isolators. However there is no evidence to suggest which at this stage – which makes HBOT so useful as it has evidence based research to support treatment across all 3 causes.

HBOT mechanisms

Hyperbaric Oxygen Therapy (HBOT) is used for chronic and urgent medical conditions associated with tissue hypoxia (lack of oxygen supply). There is growing data on physiological effects of HBOT on different injured tissue, including the brain, using different models of pre-clinical as well as clinical studies.

  • Tissue oxygenation – During HBOT, tissue oxygenation can be increased by 25-30 times. Utilizing the simple law of diffusion, the high quantity of oxygen while breathing hyperbaric oxygen, transfers from the capillary to the mitochondria in all tissues, overpassing blockage/narrowing of blood vessels.
  • HIF and the hyperoxic -normoxic paradox – The newly used HBOT protocol generates intermittent fluctuations between very high to normal oxygen levels. The mitochondria in our cells sense this relative change (from very high oxygen level back to normal level) as relative hypoxia those triggering many biological process that usually occur during hypoxia (low oxygen level), with the highest level of oxygen (hyperoxia)– the so called “Hyperoxic- Hypoxic paradox”. One of the key molecular mediators that can be triggered by the hyperoxic-hypoxic paradox is called HIF (hypoxic induced factor 1alpha). This molecule is usually triggered when the body/cell senses low level of oxygen and stress, unleashing several processes to cope with the stress. By the newly used HBOT protocol, HIF can be induced and preserved along the treatment period. Once HIF level is high, many of the regenerative processes and anti-inflammatory mechanisms are being initiated.
  • Regeneration of blood vessels (Angiogenesis) – The release of HIF in high concentration (see above) initiates a cascade of events including triggering of another molecule - VEGF (vascular endothelial growth factor) - and stem cells recruitment, leading to the generation of new blood vessels (angiogenesis). These new blood vessels are formed in the tissues where normal blood flow was decreased.
  •  Mitochondria function restoration - Both animal and human studies have shown HBOT can improve and restore the decreased mitochondrial function in different parts of our body including injured brain.
  • Downregulation of inflammatory cytokines – Research shows a decrease in IL6 with HBOT. Suppression of pro-inflammatory IL-1 family members and IL-6 have been shown to have a therapeutic effect in many inflammatory diseases, including viral infections. Covid 19 raises IL6 which in turn is linked to the genesis of idiopathic pulmonary fibrosis. [25][26][27]
  • Stem cells recruitment - HBOT induces stem cells mobilization from their storage at the bone marrow to the blood stream and from there to entire body tissues. The number of circulating stem cells increases up to 3-8 times compared to pre HBOT level. It is important to emphasize, that stem cells mobilized by HBOT home in on tissues that have suffered damage and signal a need for regeneration. In addition to mobilization, HBOT induces the differentiation of stem cells to the different tissues such as heart, muscle, kidney and brain.[14]

PVFS/CFS

The Efficacy of Hyperbaric Oxygen Therapy in the Management of Chronic Fatigue Syndrome. UHMS Journal 2013

Conclusions: We may infer that HBOT therapy decreases the severity of symptoms and increases the life quality of CFS patients. It may be a new treatment modality for the management of CFS.[16]

 

PULMONARY

Evidence from Wuhan and Louisiana has shown the beneficial effects of HBOT during Covid pneumonia.

The “ground glass” appearance of Covid pneumonia on CT cleared in 3-5 days after starting HBOT.

No patients ended up being ventilated if they were given HBOT and all patients recovered.

The HBOT relieves the oxygen debt, as well as treating the underlying inflammation in the lungs.

HBOT in Post-Covid Syndrome will oxygenate the tissues despite the lung scarring as well as treating any residual lung oedema.[17,18]

 

DELAYED NEUROPSYCHIATRIC SYNDROME

Hyperbaric Oxygen Ameliorates Delayed Neuropsychiatric Syndrome of Carbon Monoxide Poisoning

Conclusion: Our results suggest that HBOT decreases the severity of impairment in patients with DNS. Although a large randomized trial is required to address the efficacy of this therapy, therapeutic application of HBOT may be recommended in patients with DNS after CO poisoning [19]

 

HBOT has enough evidence as well as sound underlying mechanisms to trial on Post-Covid Syndrome cases.

It is a long established medical intervention and was even used in 1918 in the USA on Spanish Flu cases with good results.

As it is just oxygen delivered at an increased atmospheric pressure – it has a very low side effect profile. Ears have to be equalized as with a normal plane flight. HBOT is also safe to use on lungs and has even shown a significant increase in PEFR and FEV in one study. [20]

 

PRE-TRIAL

Before going to a full RCT, it would be pertinent to test our hypothesis first with a pre-trial.

8-10 patients. Suffering symptoms from one or more of the 3 aetiological areas.

We suggest 10 HBOT sessions, once daily at 2.4atm for 90 minutes.

Pre and post : FEV/FVC , Oximetry , IL6 and CRP , Chalder Fatigue Questionnaire – at MDC

 DLCO – at UHCW

INCLUSION

Must have tested + by PCR at the time of illness or + antibodies via Abbott serology with venous blood

Symptomatic. Health professionals preferred. 25 to 65 y.o.

EXCLUSION

2 or more recognized co-morbidities [obesity, diabetes, hypertension, asthma]

COPD or a smoker.

Claustrophobia. History of pneumothorax or epilepsy. Inability to equalize.

 

INTENTIONS FROM THE RESULTS

Current evidence shows that the sooner HBOT is initiated in COP, the lower the frequency of DNS. [23]

Assuming those “recovered” and discharged after Covid still have lung damage that can be reversed with HBOT as in the Wuhan/Louisiana trials – it is our intention to provide a protocol for the use of HBOT in the early stages of Covid recovery to prevent as well as treat these cases of Post-Covid Syndrome.

 WE WOULD BE HOPING TO SUGGEST 5 HBOT SESSIONS TO EACH DISCHARGED PATIENT AND 10 IN HOME-ISOLATED SILENT HYPOXIC DNS SUFFERERS

 

Clinical Research

Midlands Diving Chamber

www.midlandsdivingchamber.co.uk

 

  1. https://bham.onlinesurveys.ac.uk/prolonged-recovery-from-coronavirus-not-requiring-hospital-3
  2. https://www.theguardian.com/world/2020/jun/07/it-feels-endless-four-women-struggling-to-recover-from-covid-19-coronavirus-symptoms
  3. https://pubmed.ncbi.nlm.nih.gov/21435231/
  4. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/415378
  5. https://www.meassociation.org.uk/2020/04/covid-19-and-post-viral-fatigue-syndrome-by-dr-charles-shepherd-30-april-2020/
  6. https://erj.ersjournals.com/content/early/2020/05/07/13993003.01217-2020.abstract
  7. https://www.mja.com.au/journal/2020/covid-19-ards-clinical-features-and-differences-usual-pre-covid-ards
  8. https://pubmed.ncbi.nlm.nih.gov/32193638/
  9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273286/
  10. https://www.nationalgeographic.co.uk/science-and-technology/2020/05/they-dont-struggle-to-breathe-but-covid-19-is-starving-them-of
  11. https://www.news-medical.net/news/20200603/Silent-hypoxia-and-its-role-in-COVID-19-detection.aspx
  12. https://covid19-evidence.paho.org/handle/20.500.12663/1126
  13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261102/#:~:text=Delayed%20neurologic%20sequelae%20(DNS)%20are,matter%20or%20gray%20matter%20injury.
  14. https://www.shamir.org/en/unique-pages-default-aspx/the-sagol-center-for-hyperbaric-medicine-and-research/sagolaboutus/
  15. https://oem.bmj.com/content/59/10/708
  16. https://pubmed.ncbi.nlm.nih.gov/23682549/
  17. https://www.magonlinelibrary.com/doi/full/10.12968/jowc.2020.29.Sup5a.S4
  18. https://oxycamaras.com.br/wp-content/uploads/2020/04/Outcome-of-HBOT-to-COVID19.pdf.pdf.pdf.pdf.pdf
  19. https://pubmed.ncbi.nlm.nih.gov/20369650/
  20. https://bmcpulmmed.biomedcentral.com/articles/10.1186/s12890-019-0893-8
  21. https://pubmed.ncbi.nlm.nih.gov/32191587/
  22. https://erj.ersjournals.com/content/early/2020/05/07/13993003.01217-2020.abstract
  23. https://pubmed.ncbi.nlm.nih.gov/12362006/
  24. https://pubmed.ncbi.nlm.nih.gov/28847533/
  25. https://www.tandfonline.com/doi/full/10.1080/14756366.2018.1485149
  26. https://europepmc.org/article/med/28847533
  27. https://pubmed.ncbi.nlm.nih.gov/32171193/
  28. https://www.itv.com/news/2020-05-20/bikers-deliver-life-saving-devices-to-covid-19-patients-homes/
  29. https://www.theguardian.com/world/2020/may/03/happy-hypoxia-unusual-coronavirus-effect-baffles-doctors
  30. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530151/