COVID-19: Hypoxia, inflammation and immune response
Argentina Association of Hyperbaric Medicine and Research
Coronaviruses are an extensive family of viruses that can cause disease in both animals and humans. In humans, different coronaviruses cause respiratory infections that can range from the common cold to more serious illnesses such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS).
COVID-19 is the most recently discovered infectious disease caused by the coronavirus and has been declared a pandemic and global emergency by the WHO.
The most recent reports, made in Wuhan, the epicenter of the outbreak, showed that the clinical manifestations of the infection are fever, cough, and dyspnea with radiological evidence of viral pneumonia (MacLaren, 2020). Approximately 15 to 30% of patients develop Acute Respiratory Distress Syndrome (ARDS). The WHO general recommendations for ARDS treatment include the management of patients with refractory respiratory hypoxemia, for whom it recommends extracorporeal oxygenation membranes as a therapeutic resource (MacLaren, 2020).
The virus can cause death through progressive hypoxemic respiratory failure, refractory multi-organ failure, or complications such as ischemic heart failure. The need for extracorporeal oxygenation membranes is a difficult decision when the resource is limited for the high demand in this highly transmissible pandemic. Many times, it is administered to unnecessary cases to the detriment of the most acute and serious cases. The benefitrisk assessment is constant and depends on many factors.
Computed tomography scans of the lungs in patients with COVID-19 diagnosed symptoms of the progressive disease of the airspace that radiologically represents the oxygen diffusion barrier. This is how hypoxia plays a significant role in the progress of the disease, which develops its course in up to 10 weeks, with the approximate peak on day 10 in patients who manage to recover from respiratory hypoxemic failure (Li, 2020; Pan, 2020).
When COVID-19 infects the upper and lower respiratory tract, it causes a mild or upper respiratory syndrome with consequent release of inflammatory cytokines, including interleukins (IL) – 1b and IL-6. Binding of COVID-19 to the Toll-like receptor (TLR) causes the release of pro-IL-1b, which is cleaved by caspase-1, followed by activation of the inflammasome with the production of IL-1b as the main mediator of pulmonary destruction, fever, and fibrosis (Conti, 2020; Li, 2020).
Recent studies have detected that the suppression of the pro-inflammatory interleukins IL-1 and IL-6 has had therapeutic effects in many inflammatory diseases including viral infections. Furthermore, suppression of IL-1b by IL-37 in the inflammatory state induced by COVID-19 may have a new therapeutic effect in a still unknown but very promising study. The same occurs with IL-38, which is also studied as a potential therapeutic strategy for this disease (Conti, 2020; Li 2020).
Knowing and controlling the generated immune response and the inflammatory cascade that triggers the coronavirus is essential for the control and elimination of the infection. Poor adjustment of this immune response at the time of infection can result in immunopathology, inflammation, and change in pulmonary gas exchange leading to hypoxia.
Systemic and pulmonary hypoxia feeds back the exacerbated inflammation in this infection since it occurs dysfunction of the effectors of the inflammation resolution (in the inflammasome complex), such as the mitochondria. It is the producer of reactive oxygen species necessary to regulate the inflammatory process and strengthen the clearance of noxas through the respiratory burst mediated by macrophages and monocytes in the first defense line (Weinber, 2015; Hurst, 2012).
Hyperbaric Oxygenation potential role
Hyperbaric oxygen produces an increase in lung oxygenation. In the oxygen cascade and the ventilatory phase of hyperbaric oxygen therapy (HBOT), the pulmonary alveolus is the direct contact organ and the main recipient of hyperoxia (Jain, 2017). In the alveolar exchange with HBOT, the partial pressure of oxygen is increased even when it is under the pulmonary shunt and it is very useful, except in patients with chronic severe obstruction where the exchange is interrupted and there is a risk of developing hypercapnia. HBOT does not alter lung function. Even in a prospective study in healthy individuals, there were no significant changes in forced expiratory volume (FEV) and forced respiratory flow (FEF). This shows that HBOT is safe for lung function, even if it is performed chronically (Haddany, 2019).
Dr. Paul Harch suggested that the disease caused by COVID 19 was similar to lung pathology in victims of the 1918 Spanish Flu. At the time of this illness, Dr. Cunninghan treated patients with hypoxemia due to influenza. It should be noted that at that time there were no respirators, so additional oxygenation contributed significantly to resolving the hypoxemic respiratory failure in these patients.
Although the resolution of hypoxia is an important physio pathogenic factor in the development of the disease, what Dr. Cunningahn did not know at the time is that HBOT not only contributes to oxygenating tissues at the pulmonary and systemic level. Hyperoxia also has an important anti-inflammatory effect.
HBOT reduces the production and release of pro-inflammatory cytokines by neutrophils and monocytes (Gill A, 2004, Al Waili NS, 2006, Bosco G, 2018).
Studies reveal the effects of hyperbaric oxygenation on cytokine production (Al Waili NS, 2006). This therapy increases FGF production and collagen synthesis and decreases interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis alpha factor (TNF alpha). The effects of transforming beta 1 growth factor (TGFβ1) and platelet-derived growth factor (PDGFβ) are greater with HBOT (Al Waili NS, 2006, Yuan LJ, 2009).
Regarding the development of chronic inflammation, activation of the Toll-Like Receptors (TLR) system contributes to the maintenance of the inflammatory response. HBOT decreases TLR expression, NF-kB signaling pathways and the expression of these molecular platforms in different tissues (Meng XE, 2016, Wu ZS, 2018).
Furthermore, hyperbaric oxygen could increase the adaptive cellular immune response of peripheral blood mononuclear cells infected with HIV-1 virus (acquired immunodeficiency virus), through the increase of proteins that can inhibit viral replication (Budiarti R, 2018).
Given the emergency of patients with COVID-19 and the limited extracorporeal oxygenation resources, the hyperbaric chamber for infected patients suffering from respiratory hypoxemic failure could be used in cases without pulmonary contraindications for hyperbaric oxygenation therapy. In addition, it could decrease the inflammatory phase and perhaps speed up the times for recovery and release of beds required to assist these patients during the pandemic. Additional studies are needed and these hyperbaric chambers must be operated by qualified medical professionals who can carry out rigorous and reliable control of the need for other additional therapeutic requirements during the progression of the disease.
HBOT would contribute significantly to reducing morbidity, accelerating recovery times for patients suffering from the pandemic, optimizing health resources and reducing healthcare costs.
Al-Waili NS et al., Effects of hyperbaric oxygen on inflammatory response to wound and trauma: possible mechanism of action. ScientificWorldJournal. 2006; 3; 6: 425- 41.
Bosco G et al., Hyperbaric oxygen therapy ameliorates osteonecrosis in patients by modulating inflammation and oxidative stress. J Enzyme Inhib Med Chem. 2018; 33(1):1501-05.
Budiarti R et al. In Vitro Studies on Heme Oxygenase-1 and P24 antigen HIV 1 Level after Hyperbaric Oxygen treatment of HIV-1- infected on peripherical blood mononuclear cells (PBMCS). Afr J Infect Dis. 2018; 7:12(1 Suppl):1-6.
Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, Frydas I, Kritas SK.J Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by COVID-19: anti-inflammatory strategies. Biol Regul Homeost Agents. 2020 14;34(2).
Fu Y, Cheng Y, Wu Y. Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools. Virol Sin. 2020 Mar 3. doi: 10.1007/s12250-020-00207-4. [Epub ahead of print]
Gill, A. and C.N. Bell, Hyperbaric oxygen: its uses, mechanisms of action and outcomes. Qjm, 2004; 97(7): 385-95.
Hadanny A1,2,3, Zubari T4, Tamir-Adler L4, Bechor Y5, Fishlev G5, Lang E5, Polak N5, Bergan J4, Friedman M4, Efrati S Hyperbaric oxygen therapy effects on pulmonary functions: a prospective cohort study. BMC Pulm Med. 2019 13;19(1):148.
Hurst JK. What really happens in the neutrophil phagosome? Free Radic Biol Med. 2012 Aug 1;53(3):508-520.
Li W1, Cui H2, Li K1, Fang Y1, Li S3. Chest computed tomography in children with COVID-19 respiratory infection. Pediatr Radiol. 2020 11.
Li G1,2, Fan Y3, Lai Y3, Han T3, Li Z2, Zhou P1, Pan P2, Wang W1, Hu D4, Liu X5, Zhang Q1,6, Wu J1,4. Coronavirus infections and immune responses. J Med Virol. 2020 Apr;92(4):424-432. doi: 10.1002/jmv.25685. Epub 2020 Feb 7.
MacLaren G1, Fisher D2,3, Brodie D4,5. Preparing for the Most Critically Ill Patients With COVID-19: The Potential Role of Extracorporeal Membrane Oxygenation.JAMA. 2020 19.
Meng XE, Zhang Y, Li N, Fan DF, Yang C, Li H, Guo DZ, Pan SY. Hyperbaric Oxygen Alleviates Secondary Brain Injury After Trauma Through Inhibition of TLR4/NF-κB Signaling Pathway. Med Sci Monit. 2016; 26;22:284-8.
Pan F, Ye T, Sun P, Gui S, Liang B, Li L1, Zheng D1, Wang J1, Hesketh RL1, Yang L, Zheng C. Time Course of Lung Changes On Chest CT During Recovery From 2019 Novel Coronavirus (COVID-19) Pneumonia. Radiology. 2020 13:200370.
Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, Xie C, Ma K, Shang K, Wang W, Tian DS. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. 2020 Mar 12. pii: ciaa248. doi: 10.1093/cid/ciaa248. [Epub ahead of print].
Weinberg SE, Sena LA, Chandel NS. Mitochondria in the regulation of innate and adaptive immunity.Immunity. 2015 17;42(3):406-417.
Wu ZS et al. Early Hyperbaric Oxygen Treatment Attenuates Burn-Induced Neuroinflammation by Inhibiting the Galectin-3-Dependent Toll-Like Receptor- 4 Pathway in a Rat Model. Int J Mol Sci. 2018 27; 19(8).
Yuan LJ, Niu CC, Lin SS, Chan YS, Yang CY, Chen WJ, Ueng SW. Additive effects of hyperbaric oxygen and platelet-derived growth factor-BB in chondrocyte transplantation via up-regulation expression of platelet-derived growth factor-beta receptor. J Orthop Res. 2009;27(11):1439-46.
SOURCE (Spanish): https://www.aamhei.com/covid-19-hipoxia-inflamacion-y-respuesta-inmune/