key: cord-0979009-vyd724v4 authors: Shen, Chongxing; Yue, Xiaofeng; Wang, Jianwu; Shi, Chunmeng; Li, Weibing title: Nocturnal oxygen therapy as an option for early COVID-19 date: 2020-06-26 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2020.06.080 sha: 941f606a35d7e89dfe084eccfba952df31baf3b9 doc_id: 979009 cord_uid: vyd724v4 Abstract Currently, there is no effective antiviral therapy or immune-based treatments for coronavirus disease (COVID-19), and the urgent challenge is to prevent the transition of COVID-19 from mild to severe. In this paper, we provide nocturnal oxygen therapy as a new option for the patients with COVID-19 under home quarantine, and suggest that nocturnal oxygen therapy at the early stage may be helpful to prevent the disease from mild to worse by inhibiting the rapid replication of the virus and improving the body's antiviral ability. Since the first case of coronavirus disease was detected, the virus has spread rapidly and swept most countries worldwide. Currently, there is no effective antiviral therapy or immune-based treatments for COVID-19, especially for asymptomatic or mild patient, who are recommended for self-cured under home quarantine. However, the severe cases were rapidly increased from the progression of the mild cases one week after the onset and develop into respiratory failure and acute respiratory distress syndrome (ARDS) on the basis of pneumonia 1 . Therefore, the urgent challenge is to prevent the transition of COVID-19 from mild to severe. In China, oxygen therapy has been widely used and strongly recommended for patients in hospitals and cabin hospitals, however, for the asymptomatic or mild COVID-19, has not been given sufficient considerations in the present therapeutic guidelines. Through reviewing relevant literature and combining the characteristics of COVID-19, we propose that nocturnal oxygen therapy can be administrated for patients diagnosed with COVID-19 regardless of hypoxia and may be helpful to prevent the disease progression by inhibiting the rapid replication of the virus and improving the body's antiviral ability. Viruses rely on the host cell's infrastructure and metabolism to complete their life cycle. Many viruses can reprogramme host cellular metabolism for their replication. For instance, it has been shown that adenoviral, cytomegalovirus, vaccinia virus, and Kaposi's sarcoma-associated herpesvirus (KSHV) decreases oxidative phosphorylation and induces glycolysis, which provides a large carbon source for the synthesis of nucleotides and amino acids needed to replicate the virus [2] [3] [4] [5] . The mechanisms of viral activation of the glycolysis are sophisticated. Some investigations have found that hepatitis B virus，H1N1 virus，vaccinia virus, and human papillomavirus can stabilize hypoxia-inducible factor 1α (HIF-1α) from degradation under normoxic condition 4,6-8 . It is well-known that HIF-1α is a transcriptional activator of cellular metabolic state by hypoxia and stabilizing HIF-1α induces metabolic transformation from mitochondrial biogenesis to glycolysis. Furthermore, evidence also revealed that hypoxia could enhance human B19 erythrovirus gene expression and hepatitis c virus replication 9, 10 . These results indicate that HIF-1α may play a pivotal role in promoting virus replication. From the analysis of clinical data, the development of COVID-19 is a process of gradual hypoxia, which is more conducive to virus replication. However, HIF-1α activity is suppressed by hydroxylate two proline residues within HIF-1α under sufficient oxygen (O2) conditions 11 . Although there is no direct evidence that oxygen supplementation could reduce the HIF-1α expression in virus-infected cells, researchers have reported that HIF-1α expression in the kidney significantly decreased after exposure to high oxygen concentrations in vivo 12 . A recent study also showed that hyperoxic breathing of 60% O2 markedly down-regulated HIF-1α expression in tumor cells and inhibited tumor growth compared with breathing of 20% O2 13 . Thus, we speculated that early appropriate oxygen therapy for COVID-19 patients is expected to disrupt the virus replication by decreasing HIF-1α. The median time of COVID-19 patients from the initial symptom to dyspnea was 5.0 days 14 , which may be associated with cytokine storm and resulted in multi-organ damage or failure. Early robust virus replication disrupts the immune response and contributes to the subsequent inflammatory storm, while the mechanism has not been fully elucidated. For virus infection, host factors initiate an immune response against the virus. A major component of our innate immunity is the type I interferon (IFN-I) response. IFN-I can activate transcription factors and induce expression of IFN-stimulated genes 15 , thus promoting host cells to fight against the virus infection. However, SARS-CoV, which similar to SARS-CoV-2, has been proved to inhibit the production of IFN-I in cell and animal models 16 . Therefore, it is imperative to understand the mechanism of the virus to overcome the interferon response in order to take corresponding measures. Recently, researchers have demonstrated that lactate derived from glycolysis is the first metabolite directly combined with mitochondrial antiviral-signaling (MAVS), and the lactate aggregation due to glycolysis or by increased LDH may be a potential mechanism for the virus to inhibit IFN production 17 . It is worth noting that clinical studies have shown that elevated LDH or lactate levels have been detected in some patients with viral infection, especially those with poor prognosis 18, 19 . According to clinical data from patients infected with SARS-CoV-2 in Wuhan, China, LDH increased in 29/40 (73%), of which ICU care12/13 (92%) and No ICU care 17/27 (63%) 20 . Thus, inhibiting glycolysis and reducing lactate production are expected to activate antiviral immunity in the early stage of virus infection. As mentioned above, oxygen can affect the activation of HIF-1α and reduce glycolysis. In addition, oxygen could also reduce the accumulation of lactate by accelerating its degradation. Therefore, early appropriate oxygen therapy for COVID-19 patients is expected to be beneficial to release interferon and activate antiviral immune response. Immune cells such as CD8 + effector T cells and natural killer cells (NK) are believed to play a crucial role in antiviral immunity. However, the proportion of immune cells in the blood of most patients infected with SARS-CoV-2 is decreased. Recently, researchers have detected the peripheral blood lymphocyte subsets in patients with COVID-19 and found that the reduction rate of CD4+T, CD8+T and NK cells were 60.16%, 68.3% and 36.59% respectively 21 , which greatly weaken the body resistance to virus. Until now, no specific strategy has been recommended to improve the body immunity to deal with the early COVID-19. Concurrently, therapeutic effect of oxygen therapy in severe cases prompted us to the impact of oxygen on immune system. Functional T cell exhaustion has been demonstrated in patients with COVID-19, especially in severe cases, which is associated with higher levels of PD-1 22 . PD-1 was considered as a marker of T cell exhaustion and previous studies have confirmed that blocking PD-1 / PD-L1 can restore T cell function and accelerate virus clearance 23 . Recently, researchers have found that PD-L1 expression can be controlled by HIF-1α both in mouse myeloid-derived suppressor cells and in sepsis model. Silencing HIF-1a has been shown to reduce the expression of PD-L1 in monocytes and restore T cell proliferation 24, 25 . It is noteworthy that our previous analysis suggested that sufficient oxygen could reduce the HIF-1α expression，and respiratory hyperoxia has also been proved to reverse immunosuppression by decreasing PD-L1 expression levels in cancer mouse model 26 . Moreover, Kondala R. Atkuri et al reported that T cell proliferation was significantly higher at atmospheric oxygen levels (20% oxygen) than at physiological oxygen levels (5% or 10% oxygen) when lymphocytes were cultured in vitro in response to external stimuli 27 . A recent study revealed that breathing 60% oxygen increased activities of T and NK cells, and decreased immunosuppressive molecules in a murine lung cancer model 28 . Some researchers also demonstrated that lymphocytes had higher proliferation efficiency in the condition of rich-oxygen compared with hypoxia 29, 30 . Accordingly, it is tempting to speculate that sufficient oxygen may improve J o u r n a l P r e -p r o o f the antiviral ability of patients with early COVID-19 by increasing the abundance and activities of immune cells. ACE2 is a cell membrane-associated enzyme belongs to renin-angiotensin system and expressed much higher in kidney and heart than that in lung based on the date of previous report. It have been confirmed that SARS-CoV-2 uses ACE2, the same cell entry receptor of SARS-CoV, to enter the target cell 31 . Thus, previous researches on SARS-CoV may be helpful to understand the COVID-19. One study showed that SARS-CoV genome was found in the heart of 35% of the patients (7 of 20), demonstrating that heart attack was associated with earlier death 32 . The study on renal function of patients with SARS-CoV also indicated that acute renal impairment caused by SARS-CoV was related to a high mortality 33 36 . In pulmonary vascular smooth muscle cells, hypoxia was also shown to up-regulate ACE2 expression 37 . Unfortunately, researchers 38 have found that SARS-CoV infection significantly enhanced the expression of hypoxia upregulated 1gene as early as 6 h, and patient with novel coronavirus pneumonia has already appeared anoxia in the early stage. However, the symptoms of dyspnoeic do not appear until late in the disease course, which probably due to the hypoxia with accompanying hypocapnia 39 . Thus, management of hypoxia in the early stages is expected to delay the progression of COVID-19. Oxygen J o u r n a l P r e -p r o o f supplementation could increase partial pressure of O2 in arterial blood by driving pressure for O2 and improve tissue oxygenation 40 , which has been proved to improve function in the ischemic myocardium 41 . Oxygen therapy has also been reported to reduce renal vascular resistance and increases blood flow in patients with hypoxaemia 42 . Therefore, early appropriate oxygen therapy for COVID-19 patients may reduce the invasion of virus by increasing O2 content of blood against the up-regulated expression of ACE2 in tissues and organs caused by hypoxia. Since cytokine storm is currently considered to be the primary cause of acute exacerbation of COVID-19, early intervention should be taken to inhibit or reduce the excessive production of inflammatory cytokine. The production of cytokine in human whole blood shows diurnal rhythmicity. The production of pro-inflammatory cytokines including IFN-γ, TNF-a, IL-1 and IL-12 peak at night and early morning when plasma cortisol is lowest 43 . Evidence has shown whole blood stimulation with LPS in vitro, at night and early in the morning displayed increased cytokine and chemokine levels in samples from healthy volunteers compared to the daylight 44 . A subsequent study during a human in vivo has also confirmed this 45 . Furthermore, in a vesicular stomatitis virus (VSV) murine encephalitis model where mice infection occurring at the start of the rest period showed higher mortality than infected at the start of the active period and is associated with increased numbers of inflammatory cells 46 . Therefore, the reduction of nocturnal pathogen exposure or replication is expected to inhibit the production of inflammatory factors. However, the rate of virus replication in the host may accelerate at the resting phase according to Rachel S. Edgar et al, who have shown that mice infected with Murid Herpesvirus at the start of the rest phase exhibited 10-fold higher viral loads than mice infected just before their active phase 47 . However, most studies focused on the time of primary encounter with antigen. Whether virus replication is related to J o u r n a l P r e -p r o o f time-of-day, especially after virus infects the host, still requires further investigation. Moreover, a recent study has reported that SARS-CoV-2 from the nasal cavity is likely to be aspirated into the deep lung via gastro-esophageal reflex-associated aspiration, which may be an important route to lung infection and usually occurs at night 48 . Therefore, the limitation of virus replication at night would be a valid therapeutically strategy. Combined with our previous analysis, we speculated that nocturnal oxygen therapy could delay the progression of COVID-19 by inhibiting nocturnal virus replication. At present, the number of severe patients continues to increase, leading to an extremely increased demand for medical resources and comprehensive treatment. Therefore, effective and safe interventions are urgently needed to prevent the COVID-19 from mild to severe. Based on the clinical data and literature analysis, we propose that oxygen therapy can inhibit virus replication, regulate autoimmunity and decrease the ACE2 expression in tissue. Since the virus may speed up invasion at night and increase the over production of inflammatory cytokines, combined with the fact that patients with lung diseases are prone to occur hypoxia during sleep 49 , we recommend that the application of nocturnal oxygen therapy is a therapeutic option for the patients under home quarantine. Since nocturnal oxygen therapy is not a new concept and has been widely used in COPD patients, it is safe and easy to perform in clinical practice (a home oxygen concentrator is enough for a patient). 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