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Hyperbaric Oxygen Treatment For long Coronavirus Disease-19: A Case Report

By hqt / April 11, 2022

Background

Te  coronavirus  disease  2019  (COVID-19)  pandemic has resulted in a growing population of individuals who experience a wide range of long lasting symptoms after recovery from the  acute  illness,  referred to by  several terms,  including  “post-COVID  conditions”  and  “long COVID.” Te fve most common symptoms recognized post-COVID are fatigue (58%), headache (44%), cognitive impairment (27%), hair loss (25%), and dyspnea (24%) [1]. Two main biological sequelae of COVID-19 play roles in the pathogenesis of long COVID. Te frst is hyper- coagulability  state  characterized  by  increased  risk  of small- and large-vessel occlusion  [2]. Te second is an uncontrolled   continuous   infammatory   response   [3]. Microinfarcts   and   neuroinfammation   are   important causes of brain hypoxia and can be responsible for the chronic unremitting neurocognitive  decline in patients with  long  COVID  [4].  One  of the  options  to  reverse hypoxia,  reduce  neuroinfammation,  and  induce  neu- roplasticity  is  hyperbaric  oxygen  therapy  (HBOT)  [5].

In this article, we present the frst case report of previ- ously healthy, athletic individual who sufered from long- standing   post-COVID   syndrome   treated   successfully with HBOT.

Case presentation

A  55-year-old  previously  healthy  Caucasian  man  suf fering  from  persistent  unremitting  symptoms  of  long COVID attended our clinic for evaluation. Te clinical presentation included memory problems, worsening of multitasking  abilities,  fatigue,  low  energy,  breathless- ness, and reduced physical ftness, which all started after acute SARS-CoV-2 infection diagnosed 3 months before. He  initially  developed  high-grade  fever  without  chest pain, cough, or shortness of breath, on 21 January 2021. He was admitted to hospital because of dehydration on 30 January 2021 and was diagnosed with COVID-19 by reverse-transcription  polymerase  chain  reaction  (RT- PCR). During the hospital stay, he developed acute res- piratory  syndrome  due  to  pneumonitis  and  required supportive treatment with high-fow oxygen for 1 week. He was discharged from hospital on 16 February 2021. At discharge, he was stable with normal oxygen and no neurological defciencies were noted on physical exami- nation. In addition, 6 weeks after being diagnosed with COVID-19, he developed a pulmonary embolus and was treated with rivaroxaban. Prior to the SARS-CoV-2 infec- tion, he had been a healthy, high-functioning, and ath- letic individual.

Te baseline evaluation done at our clinic, 3 months after the acute infection, included brain magnetic reso- nance imaging (MRI) with perfusion and difusion tensor imaging (DTI), computerized neurocognitive evaluation, cardiopulmonary exercise test  (CPET),  and pulmonary function tests.

At  baseline,  the  patient complained  of shortness  of breath with exercise as well as difculties with memory and multitasking that started after his COVID-19 illness.

Physical and neurological examination was normal. Brain MRI  evaluation  demonstrated  reduced  perfusion  that correlated with the cognitive decline as detailed below. He was referred to hyperbaric oxygen therapy (HBOT) that  included  60  sessions,  5  days  per week.  Each  ses- sion included exposure to 90 minutes of 100% oxygen at 2  atmosphere  absolute with  5-minute  air breaks  every 20 minutes.

Te patient started his frst HBOT on  19 April 2021 and fnished on 15 July 2021 without any signifcant side efects. After the frst fve sessions, he reported that his breathing had started to improve and that he no longer had  muscle  aches  after  exercise. After  15  sessions,  he noted less fatigue and an improvement in his previous low energy. After 20 sessions, he noticed that his breath- ing and exercise capacity had returned to his capacity pre-SARS-CoV-2 infection, returning to running moun- tain trails. Additionally, he noted that his memory and multitasking ability returned to his pre-COVID-19 levels.

Te baseline brain MRI, prior to the HBOT, showed two small foci of signal alterations in the right and left parietal regions suggestive of early small vessel disease. In addition, there was a global decrease in the brain per- fusion. As detailed in Fig. 1 and Table 1, re-evaluation after HBOT (done 4 weeks after the last HBOT to avoid any potential intermediate efect) revealed a signifcant increase in brain perfusion. Tables 2 and 3 present the improvements  in  the  brain  microstructure  as  demon- strated by MRI–DTI.

Neurocognitive assessment was done using NeuroTrax full  computerized  testing  battery  to  measure  diferent aspects of brain function, such as memory, information processing speed, attention, and executive function, was done before and after HBOT. Te post-HBOT neurocog- nitive testing showed signifcant improvement in global memory with the most dominant efect being on nonver- bal memory, executive functions, attention, information procession speed, cognitive fexibility, and multitasking. Table 4 summarizes the pre- and post-HBOT scores in the diferent cognitive domains.

Physical capacity was evaluated by maximal cardiopul- monary exercise test (CPET) conducted on a COSMED treadmill using the Boston 5 protocol. Table 5 presents the pre- and post-HBOT physiological evaluated param- eters. As detailed, there was a 34% increase in the VO2 max from 3083 to 4130 mL per minute after HBOT. Te forced vital capacity (FVC) improved by 44% from 4.76 to 6.87 L, the forced expiratory volume  (FEV) by 23% from 3.87 to 4.76 L, and peak fow measurement (PEF) by 20.2% from 10.17 to 12.22 L per second.

After receiving full information at the end of his post- HBOT evaluation, the patient signed an informed con- sent allowing publication of his medical information.

Fig. 1  Brain perfusion magnetic resonance imaging before and after hyperbaric oxygen therapy. The upper row represents brain perfusion 3 months after the acute infection, before hyperbaric oxygen therapy. The lower row represents the perfusion magnetic resonance imaging done after completing the hyperbaric oxygen therapy protocol.

Table 1  Brain  blood fow changes  before and after  hyperbaric oxygen therapy

Brain region                                    PreHBOT   Post-HBOT   Change in %
White matter right (R) 19.43 22.89 17.80
White matter left (L) 19.17 22.23 16
Gray matter R 32.34 38.6 19.40
Gray matter L 33.3 38.91 16.80
Primary gustatory cortex R 34.22 47.43 38.60
Lateral postcentral gyrus R 32.08 42.79 33.40
Superior temporal gyrus R 38.04 50.65 33.10
Supramarginal gyrus R 36.37 46.39 27.60
Anterior cingulate cortex L 40.16 50.61 26
Inferior frontal gyrus L 39.47 49.6 25.70
Inferior frontal gyrus (Broca’s 37.55 46.81 24.70
area) R
Medial frontal gyrus R 29.57 36.67 24

Discussion and conclusions

Here,  we  report  the  frst  case  of a  patient  with  long COVID with cognitive and cardiorespiratory symptoms treated successfully by HBOT. Following treatment, he showed  signifcant  improvements  in  brain  perfusion, white  matter  brain  microstructure,  and  cognitive  and cardiopulmonary function. Tis case report shows that HBOT has potential use for treatment of patients with long COVID who sufer from unremitting cognitive and physical functional decline.

Hypoxia plays an important role in the pathophysiol- ogy of long COVID. Systemic hypoxia could result from lung impairment, and organ-related hypoxia can develop because  of vascular  damage.  Persisting  lung  function

Table 2  Magnetic resonance imaging–difusion tensor imaging fractional   anisotropy   changes   before   and   after   hyperbaric oxygen therapy

Brain region                                  PreHBOT    Post-HBOT    Change in %
Superior fronto-occipital fasciculus L 0.44 0.48 7.52
Cingulum (hippocampus) R 0.24 0.26 7.46
Superior corona radiata L 0.39 0.42 5.63
Body of corpus callosum 0.43 0.45 5.39
Cingulum (hippocampus) L 0.23 0.24 4.59
Corticospinal tract L 0.37 0.38 3.49
External capsule L 0.36 0.38 3.23
Superior corona radiata R 0.43 0.44 3.21

Fractional anisotropy (FA) is a measure used to evaluate white matter fber   integrity, directionality, and order. A higher value of FA indicates better fber organization. DTI difusion tensor imaging

Table 3  Magnetic resonance imaging–difusion tensor imaging mean  difusivity  changes  before  and  after  hyperbaric  oxygen therapy

Brain region                                  PreHBOT    Post-HBOT    Change in %
Medial lemniscus R 1.3 1.24 4.72
Superior longitudinal fascicu- lus L 0.76 0.73 4.61
Medial lemniscus L 1.23 1.18 4.34
Superior corona radiata L 0.77 0.74 3.18
Superior fronto-occipital

fasciculus L

0.75 0.72 3.14
Sagittal stratum L 0.83 0.81 2.51
Pontine crossing tract 0.76 0.75 2.35
Fornix L 1.01 0.99 2.06

Mean difusivity (MD) is a measure used to evaluate white matter fber density. A lower value of MD indicates a higher density. DTI difusion tensor imaging.

Table 4  Cognitive  scores  before  and  after  hyperbaric  oxygen therapy

Neurotrax  Pre-HBOT  Post-HBOT Change in %
Global cognitive score 93.3 99.4 6.5
Memory 98.8 105.8 7.1
Nonverbal memory 96.2 114 18.5
Delayed nonverbal memory 105.6 113.6 7.6
Verbal memory 92.1 94.5 2.6
Delayed verbal memory 101.3 101.3 0
Executive function 101.2 112.6 11.3
Information processing speed 74.6 80.8 8.3
Attention 87.9 92.1 4.8
Motor skills 104 105.6 1.5

Table 5  Physiological  parameters  before  and  after  hyperbaric oxygen therapy

Cardiopulmonary exercise test
VO2 max (mL/min) 3083 4130 34
VO2max/kg (mL/min/kg) 31.5 42.4 34.6
Lactic threshold (mL/min) 2941 3439 16.9
Respiratory threshold (mL/min) 3103 4076 31.4
Metabolic equivalent of task 9 12.1 34.4
(MET)
Maximal heart rate (bpm) 155 164 5.8
VO2/HR (mL per beat) 19.9 25.2 26.6
Pulmonary function tests
FVC (L) 4.76 6.87 44.3
FEV1 (L) 3.87 4.76 23
PEF (L/s) 10.17 12.22 20.2

VO2max maximum rate of oxygen consumed during exercise, ml/min milliliter      per minute, VO2max/kg maximum rate of oxygen consumed during exercise       per kilogram, ml/min/Kg milliliters per minute per kilogram, MET metabolic           equivalent of task, bpm heartbeats per minute, VO2/HR rate of oxygen consumed per heart rate, FVC forced vital capacity, L liters, FEV1 forced expiratory volume,    PEF peak fow measurement, L/s liters per second.

impairment has been seen in patients who required sup- plemental  oxygen  during  acute  SARS-CoV-2  infection even 6 and 12 months after the acute infection [6]. Since brain functionality and regenerative capacity is sensitive to any decline in oxygen supply [7], long-term cognitive defcits correlate with the amount of oxygen needed to overcome the respiratory difculties [1]. With regard to organ-related ischemia, COVID-19 induced endothelial damage and hypercoagulation, which increases the risk of vascular dysfunction responsible for the high preva- lence of myocardial infarction, ischemic strokes, and pul- monary embolism [8]. In the presented case, the patient required supportive treatment with high-fow oxygen for 1 week during the acute illness, meaning he had sufered from systemic hypoxia with its consequent risk for long- term cognitive impairment due to anoxic brain damage. Moreover, 6 weeks after the acute infection, he developed a  pulmonary  embolus,  representative  of the  endothe- lial  dysfunction  with  additional  exposure  to  systemic hypoxia. In addition, as demonstrated by the brain perfu- sion MRI, he had microvascular-related perfusion defects that correlated with his neurocognitive decline.

HBOT involves the inhalation of 100% oxygen at pres- sures  exceeding   1  atmosphere  absolute   (ATA),  thus enhancing the amount of oxygen dissolved in the body tissues.  Even  though  many  of the  benefcial  efects  of HBOT can be explained by improvement of tissue oxy- genation, it is now understood that the combined action of hyperoxia and hyperbaric pressure triggers both oxy- gen- and pressure-sensitive genes, resulting in induction of regenerative processes including stem cell proliferation and  mobilization  with  anti-apoptotic  and  anti-infam- matory factors, angiogenesis, and neurogenesis  [912]. HBOT  can  induce  neuroplasticity  and  improve  cogni- tive function even years after the acute insult [13]. In the case presented of long COVID, HBOT improved cerebral blood fow to the malperfused brain regions (indicative of brain angiogenesis) and improved the integrity of brain microstructure (indicative of neurogenesis). Te correla- tion between the signifcant improvements demonstrated on brain imaging and the neurocognitive improvements indicates that most of the benefcial efects of HBOT are indeed related to its ability to induce neuroplasticity of the brain’s dysfunctional regions.

HBOT has been demonstrated to have benefcial efects on mitochondrial function, a crucial element of appropri- ate muscle function  [12]. HBOT can also increase the number of proliferating and diferentiating satellite cells as well as the number of regenerated muscle fbers, and promote  muscle  strength  [14].  Te  newly  intermittent repeated HBOT protocol was demonstrated to have the potential to improve lung function with respect to peak expiratory fow (PEF) and force vital capacity (FVC) [15]. In the presented patient, performance capacity of the car- diopulmonary system was evaluated using cardiopulmo- nary exercise test (CPET) and pulmonary function tests. HBOT induced a signifcant improvement of 34% in the maximal oxygen consumption capacity, an improvement of 34.4% in the maximal METs, and an increase of 16.9% in the lactic threshold. With regard to lung function, FVC was improved by 44.3%, and PEF by 20.2%. Tese meas- urable improvements correlated with the patient’s ability to regain his previous high athletic performance.

In this reported case, HBOT was initiated more than 3  months  after  the  acute  SARS-CoV-2  infection.  Even though the symptoms persisted till the HBOT was ini- tiated  and  signifcant  improvement  began  only  after HBOT was initiated, it is possible that at least some of the clinical improvement could have occurred without HBOT.  However,  the  abrupt  signifcant  improvement with full recovery after the chronic nature of the symp- toms, our understanding of the physiological efects of HBOT,  and  the  objective  measurements  done  on  this patient support the relation between the treatment and the improvements seen. As this is only a case report, fur- ther prospective clinical trials are needed to gain a bet- ter  understanding  of the  potential benefcial  efects  of HBOOT for patients with long COVID.

In summary, this article represents the first case report showing that long COVID can be treated with HBOT. Te benefcial efect of HBOT sheds additional light on the pathophysiology of this syndrome. As this is a sin- gle case report, further prospective randomized control studies are needed for the use of hyperbaric oxygen ther- apy in treating long COVID.

Abbreviations

HBOT: Hyperbaric oxygen therapy; MRI: Magnetic resonance imaging; DTI: Dif- fusion tensor imaging; VO2 max: Maximum rate of oxygen consumed during   exercise; CPET: Cardiopulmonary exercise test; HR: Heart rate; Bpm: Heart beats per minute; FVC: Forced vital capacity; FEV1: Forced expiratory volume; PEF:       Peak fow measurement.

Acknowledgements

Not applicable.

Authors’ contributions

AMB, ES, SE, and SK analyzed and interpreted the patient data regarding the     MRI, perfusion, and DTI. AMB and SE analyzed and interpreted the patient data regarding the cardiopulmonary and pulmonary function tests. All authors read and approved the fnal manuscript.

Funding

No funding was received.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

AMB, ZW, SK, MG, and UQ work for AVIV Clinics. ES works for AVIV Scientifc LTD. SE is a cofounder and shareholder at AVIV Scientifc LTD.

Received: 11 October 2021   Accepted: 21 January 2022, Published online:  15, February 2022

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