The most awful complication COVID-19 is hypoxemia due to respiratory failure. The mechanisms of lung damage and hypoxemia in COVID-19 include ventilation/ perfusion mismatch, loss of hypoxic vasoconstriction and increased coagulopathy. Hence, it is of particular attention that acute lung injury, hypoxemia, systemic inflammatory response syndrome, acute respiratory distress syndrome (ARDS) occurs after SARS-CoV-2 infection. Cytokine storm in COVID-19 patients is centrally involved in the aggravation of symptoms and disease development, and denotes a key factor contributing to ARDS and mortality. Indeed, there is a close relationship between lung damage, hypoxemia and the cytokine storm. Other important issue is to consider the possible presence of happy of silent hypoxemia, which is described in patients with pronounced arterial hypoxemia who don't express a sense of dyspnea. Moreover, pulse oximetry (PO) should be interpreted with caution, because due to left-sided shifting of the oxyhemoglobin dissociation curve during hypocapnia periods, PO might measure a normal oxygen saturation in spite of very low PaO2. Continuous positive air pressure (CPAP) is nowadays the preferred method of non-invasive ventilation (NIV) management of COVID-19 patients, has significant and helpful role in Covid-19 management, mainly if it is used in an early phase of the disease, because it may prevent clinical deterioration and reduce the need for invasive ventilation at all. We strongly recommend to early use CPAP in all Covid-19 patient who present the first mild respiratory symptoms, such as cough, or light tachypnea and hyperpnea, etc., when they are still outside the ICUs, i.e. in regular wards or at patient's homes. This method would prevent periods of hypopnea and hypoxia which can stimulate the synthesis of ACE in lung endothelial cells, leading to cytokine storm, which can cause ARDS, multi-organ failure, and death.