Background: In COVID-19, an exaggerated pro-inflammatory response, known as cytokine storm (CS).  The anti-inflammatory system's CS–mediated response is an ineffective immunological control, leading to tissue damage, multiorgan failure, acute respiratory distress syndrome, and death.

Objectives: To review and discuss the tie relationship between hypoxemia and the CS, proposing an early avoidance of periods of hypoxemia to avert the CS.

Methods: We review the literature on this topic providing a pathophysiological background to support our proposal of avoiding periods of hypoxemia in the early stages of the disease.

Results: Cytokine-mediated lung endothelial and epithelial cell injury may damage the integrity of the blood–air barrier, promoting vascular permeability, alveolar edema, infiltration, and the presence of inflammatory cells, starving the blood of oxygen, causing hypoxemia. Hypoxemia triggers factors like HIF-1α, which regulates essential cellular processes, including cell proliferation, metabolism, and angiogenesis. HIF-1α is activated during the immune response and plays an indispensable role at the inflammation site by inducing pro-inflammatory cytokine production, finally resulting in CS. Short and slight periods of hypoxemia start even during the first manifestation of persistent cough and/or shortness of breath. 

Conclusion: A more straightforward treatment strategy is to provide oxygen supply as early as possible, when the first respiratory symptoms begin, to prevent periods of hypoxemia outside the ICU. We have suggested using CPAP. Other methods such as Low or High-flow nasal oxygen HFNO therapy would provide the necessary oxygen at the lung alveoli to prevent gas exchange impairment, avoid hypoxemia, and therefore, avert CS. 

A specific adaptive immune response is initiated during early incubation and non-severe stages after SARS‐CoV-2 infection to exterminate the virus and halt disease progression. The second phase is characterized by the advent of systemic symptoms with unrestrained cytokine production, known as cytokine storm (CS) [1-3].

An exaggerated pro-inflammatory characterizes CS–mediated response and ineffective control by the anti-inflammatory system, leading to tissue damage, multiorgan failure, acute respiratory distress syndrome (ARDS), and death.[4-11].

We made a detailed review of the literature regarding the relationship between hypoxemia and CS in COVID-19 disease.

Cytokine-mediated lung endothelial and epithelial cell injury may damage the integrity of the blood–air barrier, promoting vascular permeability, alveolar edema, infiltration, and the presence of inflammatory cells. As tissue breaks down, the walls of the lungs' tiny air sacs become leaky and fill with fluid starving the blood of oxygen, causing hypoxemia [12-16].

Hypoxemia triggers factors like HIF-1α, which regulates essential cellular processes, including cell proliferation, metabolism, and angiogenesis. HIF-1α is activated during the immune response and plays an indispensable role at the inflammation site by inducing pro-inflammatory cytokine production, finally resulting in CS [1-4], [17-20].

COVID-19 presents mildly in most patients, commonly beginning during the first days of clinical evolution with fever followed by a dry cough and flu‐like symptoms. Nonetheless, short and slight periods of hypoxemia start even during the first manifestation of persistent cough and/or shortness of breath, as reported by authors using pulse oximetry and arterial gasometry.21  In some cases, during the second week of the clinical evolution, these symptoms may progress, leading to ARDS, closely related to the progressive increment of CS, which requires admission in intensive care units (ICU) with mechanical ventilation [1-3], [22-26]

Hence, the medical-scientific community is desperately trying to find treatments to avert CS. Several biologic interventions targeting inflammatory cytokines or related signaling pathways have been clinically evaluated with promising results, but without a final success to defeat this disease [27-36].

Hypoxemia is a decisive triggering factor for CS in COVID-19. CS generates additional hypoxia in tissues and organs, leading to a chain reaction between hypoxemia and CS [1, 2, 8, 9, 37, 38].

Therefore, a more straightforward treatment strategy is to provide oxygen supply as early as possible, when the first respiratory symptoms begin, to prevent periods of hypoxemia outside the intensive care units. Dr. Machado has suggested using CPAP.8 Other methods such as Low or High-flow nasal oxygen HFNO therapy, administered through nasal cannulae or a mask, would provide the necessary oxygen at the lung alveoli to prevent gas exchange impairment, avoid hypoxemia, and therefore, averting CS [3, 8].

Authors declare no conflicts of interest.