Summary of the authors’ 2020 review
The pathogen responsible for the 2019 coronavirus disease pandemic primarily affects lung tissue and disrupts gas exchange, leading to acute respiratory distress syndrome, systemic hypoxia and lung injury. The search for prevention and rehabilitation methods, especially after COVID-19 pneumonia, is therefore pressing. Viral entry into lung or intestinal cells requires particular membrane conditions: structures allowing attachment, namely the ACE2 receptor, and the protein TMPRSS2. Coronaviruses such as SARS-CoV and SARS-CoV-2 are activated by TMPRSS2; inhibitors of this enzyme can therefore block the virus. ACE2 serves as the entry receptor and TMPRSS2 activates the viral S protein.
Without these structures, the COVID-19 virus cannot enter the cell. Activation of the HIF-1α signalling pathway under moderate hypoxia was found to reduce ACE2 and TMPRSS2 and increase ADAM17 on alveolocyte surfaces, consequently reducing SARS-CoV-2 invasiveness. Numerous studies provided a rationale for normobaric intermittent hypoxic–hyperoxic training. Reactive oxygen species formed during hypoxia–normoxia participate in the initial stages of intracellular redox signalling that transmits signals to the nucleus. This signalling enriches the cell with molecules protecting against damaging influences. These principles underpinned a new method and a new generation of hypoxicators supplying hyperoxic as well as hypoxic mixtures.
As an effective nonspecific method of enhancing the body’s defences, intermittent hypoxic–hyperoxic training is indispensable not only in viral-infection prevention and rehabilitation after viral pneumonia, but also in reducing disease severity if infection occurs.
Pathogenetic rationale
The 2019 coronavirus disease pandemic (COVID-19), with severe acute respiratory syndromes, and its pathogen SARS-CoV-2 became the greatest current threat to global public health. This highly infectious virus primarily affects lung tissue and disrupts gas exchange, causing acute respiratory distress syndrome and systemic hypoxia. The system oxygenating blood and therefore the whole organism is the first to be impaired [1, 2]. Rising worldwide mortality and severe complications require intensified development of treatments and prevention of consequences. Effective bronchopulmonary and cardiovascular rehabilitation after COVID-19 pneumonia should occupy a special place.
In 2019, studies by British and American scientists William Kaelin, Peter Ratcliffe and Gregg Semenza played an important role in understanding hypoxia’s pathogenetic effects on functional systems. They subsequently received the Nobel Prize in Medicine for research on cellular adaptation to oxygen shortage or absence [3, 4].
Entry of the COVID-19 virus into lung or intestinal cells requires the ACE2 receptor and the membrane-bound serine protease TMPRSS2 (transmembrane protease, serine 2), which permits viral-envelope contents to enter and activates the peplomer S protein. Since SARS-CoV and SARS-CoV-2 are activated by TMPRSS2, its inhibitors can block the virus [5, 6, 7]. SARS-CoV-2 uses angiotensin-converting enzyme 2, a membrane protein and exopeptidase, as its entry receptor, while TMPRSS2 is required for S-protein activation. Without these structures, the virus cannot enter the cell. This axiom may underpin hypoxic therapy for prevention and treatment of coronavirus-infection consequences.
T. V. Serebrovskaya and colleagues [1] hypothesized that hypoxic conditioning could activate HIF-1-induced cytoprotective signalling to reduce disease severity and improve vital-organ function in COVID-19. HIF-1 means hypoxia-inducible factor 1. They proposed that HIF-1α activation under moderate hypoxia would reduce ACE2 and TMPRSS2 activity and increase ADAM17, metalloproteinase 17, on alveolocytes, thereby reducing SARS-CoV-2 invasiveness. Conversely, HIF-1α protein targets participate in severe-hypoxia-induced proinflammatory cytokine expression and subsequent inflammation and the COVID-19 cytokine-storm phase [2, 8, 9]. It is important that moderate intermittent hypoxia doses may reduce proinflammatory processes [6].
Cytokines normally form part of the immune response to infectious agents. Severe COVID-19, however, commonly involves an excessive immune response, the cytokine storm, which damages healthy tissues. Cytokine hyperactivity can injure lungs through infiltration of inflammatory agents into interstitial tissue [10]. In severe coronavirus disease this manifests as pulmonary oedema and cardiopulmonary failure, increasing mortality risk [2, 8]. Autoimmune processes develop; white blood cells break down first and release enzymes that damage erythrocytes and platelets. Bleeding and thrombotic vascular occlusions result [11]. Released active substances lower pressure and cause blood fluid to leak into tissues.
Extensive pulmonary oedema then prevents oxygen uptake from air. Cardiac contractility falls during oxygen starvation. Dysfunction of lungs, heart, kidneys and liver constitutes multiorgan failure leading to death [2].
Severe hypoxaemia in COVID-19 is prevented and corrected by oxygenation and mechanical ventilation. Hypoxic conditioning may therefore be useful as a noninvasive, nonpharmacological method for treating the consequences of coronavirus infection [6, 12].
Hypoxia and adaptation mechanisms
Controlled hypoxia has a long history in treatment and prevention [13]. Clinical use began in the 1980s as normobaric intermittent hypoxic training. A pronounced therapeutic effect has been demonstrated in various diseases associated with hypoxaemia [14].
A recently emerging clinical discipline, mitochondrial medicine, addresses prevention and treatment of primary and secondary mitochondrial disorders [15]. Mitochondrial diseases are inherited conditions caused by defective mitochondrial function, impairing cellular energy functions. Controlled physiological hypoxia may be the most powerful means of correcting mitochondrial disorders of various origins.
Hypoxia reorganizes multiple body systems to deliver enough oxygen to tissues and adapts tissues to function during oxygen deficiency. Underlying mechanisms secure oxygen intake when environmental oxygen is scarce, supply vital organs during hypoxaemia, enable tissue oxygen utilization at low oxygen tension, and maintain ATP production through glycolytic substrate-level phosphorylation [14, 16].
Organ and tissue function and regenerative potential depend directly on energy supplied by ATP-producing mitochondria. Various diseases, including viral infections, damage mitochondria, triggering metabolic and energy disturbances unfavourable to recovery. Mitochondria also signal and act as primary oxygen-level sensors [17]; changes activate adaptation mechanisms. With altered oxygen content, for example during mountain ascent, mitochondria first initiate rapid signals, followed by slower adaptation. After 2–3 weeks in the mountains, adaptation develops. On return to sea level, cells use oxygen more economically, requiring less for the same work [14, 18]. Intermittent hypoxic–hyperoxic training enhances this effect [19, 20, 21].
Immunity destroys bacteria and viruses through an oxidative burst: accumulated intracellular oxygen is used by mitochondria and peroxisomes not for energy but to activate free radicals that destroy bacteria, viruses and even cancer cells [8]. Nitric oxide participates as an antibacterial and antiviral signalling molecule that also regulates vascular tone and cell-wall permeability [22]. Enhancing endogenous oxidative defence and nitric oxide could make cells more resistant to infection. Simultaneously, increased catalase, superoxide dismutase and peroxidase activity activates antioxidant protection [14].
Adaptation to intermittent hypoxia increases the activity of the antioxidant system, the main protector of cell membranes, and reduces membrane lipid peroxidation. This lowers permeability and improves cellular enzyme systems. University of California, Los Angeles scientists found that catalase may relieve COVID-19 symptoms by suppressing coronavirus replication and regulating cytokine production [23]. This helps prevent cytokine storm and ultimately increases resistance of cells lining pulmonary alveoli.
Patients with asymptomatic coronavirus infection were found to have increased antioxidant-enzyme activity. Their powerful immune response releases free radicals that eliminate viruses and bacteria [10]. If superoxide dismutase activity is low, however, a strong systemic inflammatory response involves the entire endothelium, with microthrombosis, impaired microcirculation and a hyperergic response ultimately causing death. Preventing this requires a large intracellular antioxidant reserve through activation of endogenous enzymes.
Intermittent hypoxic training is now widely and successfully used clinically for prevention, treatment and rehabilitation of many chronic diseases and in sport. Its potential nevertheless remains far from fully utilized [18, 24].
Clinical application and hypoxic–hyperoxic training
Mountain climate is generally considered healthy, with less illness and greater longevity. Adaptation to mountain hypoxic hypoxia has been used since 1952 following Academician N. N. Sirotinin’s proposal. From the late 1980s, R. B. Strelkov’s intermittent normobaric hypoxic therapy was used [25]. In 1992, Professor A. Z. Kolchinskaya proposed the more precise term normobaric intermittent hypoxic training, IHT, better reflecting its mechanism [14, 26].
IHT is successfully used for bronchial asthma, chronic bronchitis, cardiovascular diseases, allergy and iron-deficiency anaemia; in treatment and rehabilitation of chronic nonspecific female genital diseases; and for preventing pregnancy complications, preparing high-risk pregnant women for childbirth and preserving healthy offspring [16]. It effectively prevents complications and supports postoperative rehabilitation. Endocrinology uses it in diabetes and hypothyroidism. The Russian Ministry of Health estimates that hypoxic therapy and training reduce morbidity in these situations by 2.5–4 times [15, 17].
In the lungs, hypoxic therapy increases respiratory surface and alveolar numbers, enlarges respiratory muscle mass and induces respiratory-centre neuron hypertrophy, improving ventilation efficiency. I. Kh. Borukaeva and T. N. Tsyganova examined and treated 285 asthma patients with IHT and enteral oxygen therapy [14]. Combining hypoxic adaptation and enteral oxygen benefited mild and moderate asthma. Intermittent hypoxia improved alveolar ventilation and bronchial patency, increasing the alveolar fraction of minute ventilation and reducing functional dead space. Exhaled-breath condensate composition and quantity indicated normalized mucociliary clearance and improved pulmonary metabolism, reflecting less hypoxia from both compensatory IHT responses and oxygen therapy’s bronchial effects.
Oxygen cocktails combined with hypoxic therapy improved all links of the functional system and normalized patients’ oxygen regimen. Normalization of respiratory function and oxygen status improved the clinical course and prolonged remission. Thus combined IHT and enteral oxygen therapy can successfully treat mild and moderate asthma [27, 28, 29].
Hypoxic therapy is therefore not a treatment or prevention method for one particular disease. It enhances nonspecific resistance, thereby contributing to treatment and prevention of many diseases, resistance to adverse influences, and improved physical and mental performance [14].
Intermittent hypoxic–hyperoxic training entered medical practice in 2010. Adaptation uses periodic exposure to gas environments with oxygen below and above normal, alternating hypoxia and hyperoxia. Resistance develops not only from hypoxia itself but also from the transition to normoxia, reoxygenation. Reactive oxygen species arise during this transition and have damaging effects at high concentrations [30, 31].
Recent work shows that ROS initiate intracellular redox signalling to the nucleus. This enriches the cell with protective molecules, and endogenous protection formed within the cell is much more effective than external supplementation. A concept was developed linking ROS to enhanced nonspecific resistance under periodic exposure [32, 33]. The free-radical signal during adaptation increases cellular resistance to diverse damaging factors. Its intensity can be enhanced by adding hyperoxia rather than deepening hypoxia, providing a key rationale for the next generation of hypoxicators [34].
Periodic hypoxia and hyperoxia increase human compensatory capacity. Adaptation to their combined use has a pronounced protective effect and develops substantially earlier than adaptation using hypoxic periods alone [35].
Recovery after infection
Another important aspect of coronavirus infection is inflammatory severity, potentially fulminant and sepsis-like with a very poor prognosis. Older people, especially those with bronchopulmonary and cardiovascular comorbidities, are at risk. Preventive expansion of these systems’ functional reserves may decisively influence disease severity and prognosis [11].
Pulmonary inflammation can persist for weeks, followed by fibrosis at damaged sites. Cardiac, respiratory, digestive or renal comorbidities may exacerbate after coronavirus recovery because of general weakness and immune disturbances. This demonstrates the absolute need for effective bronchopulmonary and cardiovascular rehabilitation after COVID-19 pneumonia. Adaptation through IHT has proved highly effective in improving patients after pneumonia. Persistent hypoxia means thrombosis followed by stroke or infarction, an acute condition such as blood loss, or a viral infection [36].
Intermittent hypoxic–hyperoxic training is recognized internationally as increasing nonspecific resistance to pathological environmental factors, including infectious ones [16]. This non-drug equipment-based treatment, prevention and rehabilitation method has been used domestically since 1982. It alternates breathing mixtures with reduced oxygen, 9–16% O₂, and increased oxygen, up to 37% [37, 39].
The Russian Ministry of Health has issued interim guidelines on prevention, diagnosis and treatment of novel coronavirus infection [39]. The stage-two rehabilitation section recommended normobaric hypoxic therapy to oxygenate tissues, increase organ blood flow, improve tissue respiration and reduce alveolar hypoxia, with contraindications taken into account.
Equipment and the authors’ conclusion
For these purposes, the HYPO-OXY-1 unit, trademark OXYTERRA, was developed under patent 2301686 of 2007 for a hypoxic/hyperoxic therapy apparatus [40]. From ambient air it produces hypoxic mixtures containing 7–21% oxygen and hyperoxic mixtures up to 37% O₂. Additional instruments, a volumeter, pulse oximeter, heart-rate-variability and ST-segment measurements, permit assessment of tidal volume, minute ventilation, respiratory frequency, maximal ventilation, HR and haemoglobin saturation, with continuous ECG monitoring and ST-segment analysis [36].
This suggests use not only for IHT but also as a diagnostic instrument to assess and monitor patients. The device has now completed practically all tests, received registration certificate 2009/06438 and entered industrial production.
Thus, intermittent hypoxic–hyperoxic training, as an effective nonspecific means of enhancing the body’s defences, is indispensable in viral-infection prevention and rehabilitation after viral pneumonia, and in reducing severity if infection occurs. Importantly, combined hypoxia and hyperoxia produce a more pronounced rise in blood oxygen saturation and oxygen-carrying capacity.
References
Серебровская З.О.., Чонг Э.Ю., Серебровская Т.В., Тумановская Л.В., Лэй Си . Гипоксия, HIF-1α и COVID-19: от патогенных факторов к потенциальным терапевтическим мишеням // Acta Pharmacologica Sinica. –М, 2020.-С.1-8.
Цюй Е ., В а н Б., Мао Дж., Патогенез и лечение «Цитокин шторм» в COVID-19 // J.Infect., 2020. –v. 80. – P. 607-613.
Semenza G.L. Perspectives on oxygen sensing // Cell, 1999. -v.98. -P.281-284.
Semenza G.L. Signal transduction to hypoxia-inducible factor // J. Biochem. Pharmacol., 2002. -v.64. -P.993-998.
Hoffmann M., Kleine-Weber H., Schroeder S. et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor // Cell, 2020. – v.181 (2). –P. 271.
Maulik, N. Engelman R.M., Rouson J.A. et al. Ischemic preconditioning reduces apoptosis by up regulating Anti-death gene Bcl-2 // Circulation,1999. -v.100 (Suppl 2). -P.369-375.
Paoloni-Giacobino A., Chen H., Peitsch M.C., Rossier C., Antonarakis S.E. Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22.3 // Genomics, 1997. –v. 44 (3). –P. 48- 56.
Хосе Р.Дж, Мануэль А. Цитокиновый штормCOVID-19: взаимодействие между f lамация и коагуляция //Ланцет. Респир. Мед., 2020; -т.8.–е46-e47.
Цюй Е ., В а н Б., Мао Дж . Патогенез и лечение «Цитокин шторм» в COVID-19 //J.Infect., 2020. –v. 80.– P. 607-613.
Yu J., Yu J., Mani R.S., CaoQ.et al. An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression // Cancer Cell., 2010. – v.17 (5).–P. 443-449.
Чжоу Ф., Ду Р., Фан Дж . и др. Клинические течения и факторы риска 138 госпитализированных пациентов с пневмонией с COVID-19 в Ухане. Китай: ретроспективное когортное исследование // Ланцет, 2010. –т.395. –С. 1054-1062.
Burtscher M ., Pachinger O., Ehrenburg I. Intermittent hypoxia increases exercise tolerance in elderly men with and without coronary artery disease // International Journal of Cardiology, 2004. –v. 96(2). –P. 247-254.
ЦыгановаТ.Н. Экскурс в развитии науки о гипоксии //Физиотерапевт, 2015. – №5. – С. 76-84.
Колчинская А.З., Цыганова Т.Н., Остапенко Л.А.Интервальная гипоксическая тренировка в медицине и спорте. М.: Медицина, 2003. -407с.
Царегородцев А.Д., Сухоруков В.С. Митохондриальная медицина – проблемы и задачи //Российский вестник перинатологии и педиатрии, 2012.-т.4(2). -С.4-12
Цыганова Т.Н. Автоматизированный анализ эффективности и механизмы действия нормобарической интервальной гипоксической тренировки в восстановительной коррекции функциональных резервов организма. Дисс…д.м.н., М.: 2004. -289 с.
Цыганова Т.Н., Прокопов А.Ф. Использование метода гипо-гиперокситерапии в практике митохондриальной медицины (обзорная статья)// Физиотерапевт, 2016.-№3. -С.15- 22.
Колчинская А.З. Интервальная гипоксическая тренировка -эффективность, механизмы действия. – Киев, 1992.-159 с.
АрхипенкоЮ.В. Гипоксия и реоксигенация: плюсы и минусы активации кислорода: Матер. 2-й Всерос. конф. М., 1999.-С.6-7.
Анчишкина Н.А.,Жукова А.Г., Бедарева И.В. и др. Роль активных форм кислорода и редокс сигнализации в защитных эффектах адаптации к изменению уровня кислорода // Физиологический журнал, 2008.-т.54. -№ 2.-С. 12-29.
Сазонтова Т.Г., Жукова А.Г., АнчишкинаН.А., Архипенко Ю.В. Фактор транскрипции HIF-la, белки срочного ответа и резистентность мембранных структур в динамике после острой гипоксии // Вестник РАМН, 2007. -№ 2.-С.17-25.
Манухина, Е.Б.,Малышев И. Ю. Роль оксида азота в защитных эффектах адаптации // Адаптационная биология и медицина. Под ред. Я. Моравца, Н. Такеда, П. К. Сингала. Издательство "Нароса". – Нью-Дели, 2002. –т. 3. –С. 312- 327.
Common antioxidant enzyme may provide potential treatment for COVID-19 by University of Colifornia, Los Angeles. Advanced materials, 09.2020.
Радзиевский П.А. Гипобарическая гипоксическая тренировка в спорте. Автоматизированный анализ эффективности использования адаптации к гипоксии в медицине и спорте. Нальчик, 2001. -т.1.-185с.
Стрелков Р.Б. Метод повышения неспецифической резистентности организма с помощью нормобарической гипоксической стимуляции. Метод, рекомендации МЗ СССР. – М., 1985.-10 с.
Цыганова Т.Н. Эффективность интервальной гипоксической тренировки в спорте (обзорная статья) // Лечебная физкультура и спортивная медицина, 2015.–№ 6. –С. 47- 54.
Безносов С.Г., Огородова Л.М.., Сальникова В.А. Клиническая оценка метода ИГТ в комплексной терапии бронхиальной астмы у детей //J.HypoxiaMedical, 1994.–№ 2. –С.59- 66.
Борукаева И.Х., Цыганова Т.Н. Комбинированное применение гипокситерапии и оксигенотерапии в санаторно -курортном лечении бронхиальной астмы// Вопросы курортологии, физиотерапии и лечебной физической культуры, 2012.–№ 4.–С. 10- 14.
Хэ Г., Хан Й., Фанг Q. и др. Кислородная терапия назальной канюли у пациентов с тяжелой коронавирусной болезнью 2019 (COVID 19) // Клинический опыт, 2020.–т49. –С. 232- 239.
Haider T., Casucci G., Linser T. et al. Interval hypoxic training improves autonomic cardiovascular and respiratory control in patients with mild chronic obstructive pulmonary disease // J. Hypertens., 2009. –v. 27(8). –P. 115- 124.
Сазонтова Т.Г., Анчишкина Н.А., Жукова А.Г. и др. Рольактивных форм кислород и редокссигнализации в защитных эффектах адаптации к изменению уровня кислорода //Фiзiологiчний журнал, 2008.-т.54. -№ 2. –С.12-29.
Arkhipenko Y., Vdovina I., Kostina N., SazontovaТ., Glazachev O. Adaptation to interval hypoxia-hyperoxia improves exercise tolerance in professional athletes: experimental substantiation and applied approbation // European Scientific Journal., 2014. -v.10.-P. 135-154.
Sazontova T.G., Zhukova A.G., Anchishkina N.A., Arkhipenko Yu.V. HIF -la Transcription Factor and Urgent Response Proteins in Acute Hypoxia and Adaptation. Abstracts of the 5thInternational Congress of Pathophysiology, Beijing, China. 2006. June 28- July 1 // Chinese Journal of Pathophysiology, 2006. -v.22. -№ 3 (Suppl.). -Р.1-14.
Сазонтова Т.Г., Болотова А. В., Костина Н.В., Хайруллина А.А., Архипенко Ю.В. Адаптация к гипоксии и гипероксии предупреждает развитие стрессорных состояний при действии малых доз токсикантов // Материалы 6 Росс. конф. с межд. участием Гипоксия: механизмы, адаптация, коррекция. Изд. НИИОППФ. -М, 2011.-С.23-26.
Архипенко Ю.В., Сазонтова Т.Г., Глазачев О.С., Платоненко В.И. Патент на изобретение «Способ повышения неспецифических адаптационных возможностей человека на основе гипоксически-гипероксических газовых смесей», 2006. № 2289432.
Солкин А.А., Белявский Н.Н., Кузнецов В.И., Николаева А.Г. Основные механизмы формирования защиты головного мозга при адаптации к гипоксии // Вестник ВГМУ, 2012.–т. 11.–С.6-14.
Цыганова Т.Н. Нормобарическая интервальная гипо-гипероксическая тренировка – обоснование создания нового поколения гипоксикатора – гипоокси-1(обзорная статья) // Russian Journal of Rehabilitation Medicine, 2019.–№1. –С.47-66.
Глазачев О. С, Звенигородская Л. А., Дудник Е. Н. и др. Интервальные гипо-гипероксические тренировки в лечении метаболического синдрома// Экспериментальная и клиническая гастроэнтерология, 2010.-№7.–С. .33-37.
Временные методические рекомендации – профилактика, диагностика и лечение новой короновирусной инфекции ( COVID-19) Версия 9 (26.10.2010) Министерства здравоохранения РФ.
Цыганова Т.Н., Бобровницкий И.П. «Аппарат для гипо-, гиперокситерапии». Патент № 2301686, 2007.
Full main-text translation of the authors’ review: Т.Н. Цыганова, В.К. Фролков. Патогенетическое обоснование применения гипо-гипероксической тренировки в лечении и профилактике осложнений коронавирусной инфекции COVID-19. Авторский материал 2020 года, 12 с.
Related resources
Related resources on technology, equipment and applications.