Unraveling the Underlying Molecular Mechanism of 'Silent Hypoxia' in COVID-19 Patients Suggests a Central Role for Angiotensin II Modulation of the AT1R-Hypoxia-Inducible Factor Signaling Pathway.

A few days after being infected with SARS-CoV-2, a fraction of people remain asymptomatic but suffer from a decrease in arterial oxygen saturation in the absence of apparent dyspnea. In light of our clinical investigation on the modulation of molecules belonging to the renin angiotensin system (RAS) in COVID-19 patients, we propose a model that explains 'silent hypoxia'. The RAS imbalance caused by SARS-CoV-2 results in an accumulation of angiotensin 2 (Ang II), which activates the angiotensin 2 type 1 receptor (AT1R) and triggers a harmful cascade of intracellular signals leading to the nuclear translocation of the hypoxia-inducible factor (HIF)-1α. HIF-1α transactivates many genes including the angiotensin-converting enzyme 1 (ACE1), while at the same time, ACE2 is downregulated. A growing number of cells is maintained in a hypoxic condition that is self-sustained by the presence of the virus and the ACE1/ACE2 ratio imbalance. This is associated with a progressive worsening of the patient's biological parameters including decreased oxygen saturation, without further clinical manifestations. When too many cells activate the Ang II-AT1R-HIF-1α axis, there is a 'hypoxic spillover', which marks the tipping point between 'silent' and symptomatic hypoxia in the patient. Immediate ventilation is required to prevent the 'hypoxic spillover'.

[Acute rehabilitation after COVID-19 infection : A selected case series]. / Akutrehabilitation nach COVID­19­Infektion : Eine ausgewählte Fallserie.

BACKGROUND: While the first wave of the coronavirus disease 2019 (COVID-19) pandemic mainly affected the old, currently younger patients also become infected and hospitalized. After severe and critical COVID-19 infections and also after surviving acute phase symptoms, these patients often show symptoms (e.g. exertional dyspnea), organ damage (e.g. of the lungs, the cardiovascular system) as well as psychological impairments. OBJECTIVE: The severe courses after critical cases of COVID-19 represent challenges for rehabilitation and require more than ever rehabilitative treatment approaches even in acute hospitals. METHODS: This article presents a selected case series of patients with a typical constellation of pre-existing conditions due to immunosuppression plus critical course of COVID-19 and indications for acute rehabilitation. RESULTS: This case series depicts the long duration of hospitalization with high numbers of hours on ventilation in the intensive care unit. At the time of transfer to acute rehabilitation these patients are immobile and have severe limitations in all activities of daily life, so that an inpatient rehabilitation in an acute hospital is indicated and the usual means of continuation of rehabilitation were not feasible. The sequelae of lying prone and complications, such as exertional desaturation in the early stage of convalescence are detected in the acute phase of early rehabilitation. CONCLUSION: After severe COVID-19 infections new challenges for rehabilitation are to be expected, so that rehabilitative treatment approaches with an interdisciplinary early rehabilitation in an acute hospital are urgently needed. Finally, acute rehabilitation not only enables a seamless treatment chain for these patients but also the flow of patients from the intensive care unit to ensure the functioning of local infrastructures.

Respiratory Drive, Dyspnea, and Silent Hypoxemia: A Physiological Review in the Context of COVID-19.

Infection with SARS-CoV-2 in select individuals results in viral sepsis, pneumonia, and hypoxemic respiratory failure, collectively known as COVID-19. In the early months of the pandemic, the combination of novel disease presentation, enormous surges of critically ill patients, and severity of illness lent to early observations and pronouncements regarding COVID-19 that could not be scientifically validated owing to crisis circumstances. One of these was a phenomenon referred to as "happy hypoxia." Widely discussed in the lay press, it was thought to represent a novel and perplexing phenomenon: severe hypoxemia coupled with the absence of respiratory distress and dyspnea. Silent hypoxemia is the preferred term describing an apparent lack of distress in the presence of hypoxemia. However, the phenomenon is well known among respiratory physiologists as hypoxic ventilatory decline. Silent hypoxemia can be explained by physiologic mechanisms governing the control of breathing, breathing perception, and cardiovascular compensation. This narrative review examines silent hypoxemia during COVID-19 as well as hypotheses that viral infection of the central and peripheral nervous system may be implicated. Moreover, the credulous embrace of happy hypoxia and the novel hypotheses proposed to explain it has exposed significant misunderstandings among clinicians regarding the physiologic mechanisms governing both the control of breathing and the modulation of breathing sensations. Therefore, a substantial focus of this paper is to provide an in-depth review of these topics.

Predictors of silent hypoxia in hospitalized patients with COVID-19 in Japan.

INTRODUCTION: Silent hypoxia (SH) is common in patients with coronavirus disease (COVID-19) in Japan and other countries. Early identification of SH is important as more treatment options for COVID-19 have become available. This study aimed to identify predictors of SH using a nationwide COVID-19 registry of hospitalized patients. METHODS: Adult patients who were admitted to hospital with COVID-19 between January 2020 and June 2021 and who were hypoxic on admission (SpO2: 70-93%), not transferred from another facility, and who did not have disturbance of consciousness, confusion, or dementia, were included. SH was defined as hypoxia in the absence of shortness of breath/dyspnea upon admission. Predictors of SH were identified using univariable and multivariable logistic regression. RESULTS: The study included 1904 patients, of whom 990 (52%) satisfied the criteria for SH. Compared to patients without SH, patients with SH were older, more likely to be female, and had a slightly higher SpO2 on admission. Compared to patients without SH, patients with SH had a lower prevalence of chronic lung disease (CLD) other than chronic obstructive pulmonary disease (COPD), asthma, and obesity. Multivariable analysis revealed that the independent predictors of SH were older age, a shorter interval from symptom onset to admission, higher SpO2, and an absence of CLD or COPD. CONCLUSIONS: The absence of underlying lung disease and older age were important predictors of SH. The results of this study, which is the largest such study reported to date in Japan, may help clarify the mechanism of SH.

Silent Hypoxia in Coronavirus disease-2019: Is it more dangerous? -A retrospective cohort study.

Background: Hypoxia in patients with COVID-19 is one of the strongest predictors of mortality. Silent hypoxia is characterised by the presence of hypoxia without dyspnoea. Silent hypoxia has been shown to affect the outcome in previous studies. Methods: This was a retrospective study of a cohort of patients with SARS-CoV-2 infection who were hypoxic at presentation. Clinical, laboratory and treatment parameters in patients with silent hypoxia and dyspnoeic hypoxia were compared. Multivariate logistic regression models were fitted to identify the factors predicting mortality. Results: Among 2080 patients with COVID-19 admitted to our hospital, 811 patients were hypoxic with SpO2 <94% at the time of presentation. Among them, 174 (21.45%) did not have dyspnoea since the onset of COVID-19 symptoms. Further, 5.2% of patients were completely asymptomatic for COVID-19 and were found to be hypoxic only on pulse oximetry. The case fatality rate in patients with silent hypoxia was 45.4% as compared to 40.03% in dyspnoeic hypoxic patients (P = 0.202). The odds ratio of death was 1.1 (95% CI: 0.41-2.97) in the patients with silent hypoxia after adjusting for baseline characteristics, laboratory parameters, treatment and in-hospital complications, which did not reach statistical significance (P = 0.851). Conclusion: Silent hypoxia may be the only presenting feature of COVID-19. As the case fatality rate is comparable between silent and dyspnoeic hypoxia, it should be recognised early and treated as aggressively. Because home isolation is recommended in patients with COVID-19, it is essential to use pulse oximetry in the home setting to identify these patients.

Risk factors associated with asymptomatic hypoxemia among COVID-19 patients: a retrospective study using the nationwide Japanese registry, COVIREGI-JP.

Deaths of home-care patients with coronavirus disease (COVID-19) have become a social problem. One of their causes is hypoxemia without dyspnea which delays seeking medical attention. This was a retrospective study including patients registered in the COVID-19 Registry Japan, in which hospitalized patients with COVID-19 in 227 participating healthcare facilities were enrolled. The enrolled patients were divided into two groups: non-dyspneic patients with a peripheral capillary oxygen saturation (SpO2) ≤ 93% on admission (the hypoxemia without dyspnea group) and non-dyspneic patients with an SpO2> 93% (the control group). We conducted a multivariate logistic regression analysis to identify the factors associated with hypoxemia without dyspnea. 21544 patients were enrolled, 1035 (4.8%) patients were in the hypoxemia without dyspnea group, and 20509 (95.2%) patients were in the control group. The median respiratory rate (RR) of the hypoxemia without dyspnea group was higher than that of the control group (31/min vs. 18/min, p < 0.001). Age> 65, male, body mass index> 25, smoking, chronic obstructive pulmonary disease, other chronic lung disease, and diabetes mellitus were the independent factors associated with hypoxemia without dyspnea. Patients with those background should be closely monitored. RR is an important indicator of hypoxemia, even in the absence of dyspnea.

The impact of remote home monitoring of people with COVID-19 using pulse oximetry: A national population and observational study.

BACKGROUND: Remote home monitoring of people testing positive for COVID-19 using pulse oximetry was implemented across England during the Winter of 2020/21 to identify falling blood oxygen saturation levels at an early stage. This was hypothesised to enable earlier hospital admission, reduce the need for intensive care and improve survival. This study is an evaluation of the clinical effectiveness of the pre-hospital monitoring programme, COVID oximetry @home (CO@h). METHODS: The setting was all Clinical Commissioning Group (CCG) areas in England where there were complete data on the number of people enrolled onto the programme between 2nd November 2020 and 21st February 2021. We analysed relationships at a geographical area level between the extent to which people aged 65 or over were enrolled onto the programme and outcomes over the period between November 2020 to February 2021. FINDINGS: For every 10% increase in coverage of the programme, mortality was reduced by 2% (95% confidence interval:4% reduction to 1% increase), admissions increased by 3% (-1% to 7%), in-hospital mortality fell by 3% (-8% to 3%) and lengths of stay increased by 1·8% (-1·2% to 4·9%). None of these results are statistically significant, although the confidence interval indicates that any adverse effect on mortality would be small, but a mortality reduction of up to 4% may have resulted from the programme. INTERPRETATION: There are several possible explanations for our findings. One is that CO@h did not have the hypothesised impact. Another is that the low rates of enrolment and incomplete data in many areas reduced the chances of detecting any impact that may have existed. Also, CO@h has been implemented in many different ways across the country and these may have had varying levels of effect. FUNDING: This is independent research funded by the National Institute for Health Research, Health Services & Delivery Research programme (RSET Project no. 16/138/17; BRACE Project no. 16/138/31) and NHSEI. NJF is an NIHR Senior Investigator.

Use of home pulse oximetry with daily short message service messages for monitoring outpatients with COVID-19: The patient's experience.

Studies have shown COVID-19 patients may have a low oxygen saturation (SpO2) independent of visible respiratory distress, a phenomenon termed "silent hypoxia." Silent hypoxia creates uncertainty in the outpatient setting for clinicians and patients alike. In this study, we examined the potential for pulse oximeters in identifying early signs of clinical deterioration. We report descriptive results on COVID-positive patients' experiences with a comprehensive home monitoring tool comprised of home SpO2 measurements with a novel symptom-tracking short message service/text messaging application. Of patients who required hospitalization, 83% sought care as a result of low pulse oximeter readings. Nearly all patients who did not require hospitalization reported that having a pulse oximeter provided them with the confidence to stay at home. Essentially all patients found a home pulse oximeter useful. Keeping COVID-19-positive patients at home reduces the potential for disease spread and prevents unnecessary costs and strain on the healthcare system.

The Misattributed and Silent Causes of Poor COVID-19 Outcomes Among Pregnant Women.

Abundant evidence strongly suggests that the condition of pregnancy makes women and their fetuses highly vulnerable to severe Corona-virus 2019 (COVID-19) complications. Here, two novel hypoxia-related conditions are proposed to play a pivotal role in better understanding the relationship between COVID-19, pregnancy and poor health outcomes. The first condition, "misattributed dyspnea (shortness of breath)" refers to respiratory symptoms common to both advanced pregnancy and COVID-19, which are mistakenly perceived as related to the former rather than to the latter; as a result, pregnant women with this condition receive no medical attention until the disease is in an advanced stage. The second condition, "silent hypoxia", refers to abnormally low blood oxygen saturation levels in COVID-19 patients, which occur in the absence of typical respiratory distress symptoms, such as dyspnea, thereby also leading to delayed diagnosis and treatment. The delay in diagnosis and referral to treatment, due to either "misattributed dypsnea" or "silent hypoxia", may lead to rapid deterioration and poor health outcome to both the mothers and their fetuses. This is particularly valid among women during advanced stages of pregnancy as the altered respiratory features make the consequences of the disease more challenging to cope with. Studies have demonstrated the importance of monitoring blood oxygen saturation by pulse oximetry as a reliable predictor of disease severity and outcome among COVID-19 patients. We propose the use of home pulse oximetry during pregnancy as a diagnostic measure that, together with proper medical guidance, may allow early diagnosis of hypoxia and better health outcomes.

Case Report: The Carotid Body in COVID-19: Histopathological and Virological Analyses of an Autopsy Case Series.

Various authors have hypothesized carotid body (CB) involvement in Coronavirus Disease 2019 (COVID-19), through direct invasion or indirect effects by systemic stimuli ('cytokine storm', angiotensin-converting enzyme [ACE]1/ACE2 imbalance). However, empirical evidence is limited or partial. Here, we present an integrated histopathological and virological analysis of CBs sampled at autopsy from four subjects (2 males and 2 females; age: >70 years old) who died of COVID-19. Histopathological, immunohistochemical and molecular investigation techniques were employed to characterize Severe Acute Respiratory Syndrome - Coronavirus 2 (SARS-CoV2) viral invasion and inflammatory reaction. SARS-CoV2 RNA was detected in the CBs of three cases through Real-Time Reverse Transcription Polymerase Chain Reaction (RT-PCR). In these cases, positive immunostaining for Nucleocapsid and Spike protein were also demonstrated, mainly at the level of large roundish cells consistent with type I cells, confirming direct CB invasion. In these cases, T lymphocytes showed focal aggregations in the CBs, suggestive of local inflammatory reaction. Blood congestion and microthrombosis were also found in one of the positive cases. Intriguingly, microthrombosis, blood congestion and microhaemorrages were also bilaterally detected in the CBs of the negative case, supporting the possibility of COVID-19 effects on the CB even in the absence of its direct invasion. SARS-CoV-2 direct invasion of the CB is confirmed through both immunohistochemistry and RT-PCR, with likely involvement of different cell types. We also reported histopathological findings which could be ascribed to local and/or systemic actions of SARS-CoV-2 and which could potentially affect chemoreception.

Predictors and clinical outcomes of silent hypoxia in COVID-19 patients, a single-center retrospective cohort study.

BACKGROUND: Patients with COVID-19 usually present with fever and respiratory symptoms such as cough, sputum production, and dyspnea. However, they may suffer from severe hypoxemia without a clinical correlation with the respiratory symptoms, also known as silent or apathetic hypoxia. The aim of the study was to assess the predictors and clinical outcomes of COVID-19 patients without dyspnea. METHODS: A single-center retrospective cohort study, based on data extracted from the electronic hospital information system, with COVID-19 patients over a 10-month period in Riyadh, Saudi Arabia. RESULTS: Of the COVID-19 patients presenting at the Emergency Department with a SpO2 < 90%, 13% had silent hypoxia. The majority of the patients required BiPAP, 34% were intubated and 60% were admitted to an intensive care unit. There was no association between dyspnea and gender, age group, body mass index, or comorbidity. Cough, fever, and chronic cardiac diseases were predictive for dyspnea in a regression analysis. There was no difference in the clinical outcome between patients with silent dyspnea or dyspnea. Age and obesity were significantly associated with a decrease in survival, and an increase in the initial SpO2 increased survival. CONCLUSION: Patients with cardiac disease are more likely to present with silent hypoxia. The SpO2 saturation in COVID-19 may be an independent predictor of survival. Silent hypoxia in COVID-19 patients does not appear to have an association with increase in mortality.

Early Detection of Symptom Exacerbation in Patients With SARS-CoV-2 Infection Using the Fitbit Charge 3 (DEXTERITY): Pilot Evaluation.

BACKGROUND: Some patients with COVID-19 experienced sudden death due to rapid symptom deterioration. Thus, it is important to predict COVID-19 symptom exacerbation at an early stage prior to increasing severity in patients. Patients with COVID-19 could experience a unique "silent hypoxia" at an early stage of the infection when they are apparently asymptomatic, but with rather low SpO2 (oxygen saturation) levels. In order to continuously monitor SpO2 in daily life, a high-performance wearable device, such as the Apple Watch or Fitbit, has become commercially available to monitor several biometric data including steps, resting heart rate (RHR), physical activity, sleep quality, and estimated oxygen variation (EOV). OBJECTIVE: This study aimed to test whether EOV measured by the wearable device Fitbit can predict COVID-19 symptom exacerbation. METHODS: We recruited patients with COVID-19 from August to November 2020. Patients were asked to wear the Fitbit for 30 days, and biometric data including EOV and RHR were extracted. EOV is a relative physiological measure that reflects users' SpO2 levels during sleep. We defined a high EOV signal as a patient's oxygen level exhibiting a significant dip and recovery within the index period, and a high RHR signal as daily RHR exceeding 5 beats per day compared with the minimum RHR of each patient in the study period. We defined successful prediction as the appearance of those signals within 2 days before the onset of the primary outcome. The primary outcome was the composite of deaths of all causes, use of extracorporeal membrane oxygenation, use of mechanical ventilation, oxygenation, and exacerbation of COVID-19 symptoms, irrespective of readmission. We also assessed each outcome individually as secondary outcomes. We made weekly phone calls to discharged patients to check on their symptoms. RESULTS: We enrolled 23 patients with COVID-19 diagnosed by a positive SARS-CoV-2 polymerase chain reaction test. The patients had a mean age of 50.9 (SD 20) years, and 70% (n=16) were female. Each patient wore the Fitbit for 30 days. COVID-19 symptom exacerbation occurred in 6 (26%) patients. We were successful in predicting exacerbation using EOV signals in 4 out of 5 cases (sensitivity=80%, specificity=90%), whereas the sensitivity and specificity of high RHR signals were 50% and 80%, respectively, both lower than those of high EOV signals. Coincidental obstructive sleep apnea syndrome confirmed by polysomnography was detected in 1 patient via consistently high EOV signals. CONCLUSIONS: This pilot study successfully detected early COVID-19 symptom exacerbation by measuring EOV, which may help to identify the early signs of COVID-19 exacerbation. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry UMIN000041421; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000047290.

Clinical and radiological findings of silent hypoxia among COVID-19 patients.

The aim of this study was to describe the clinical and radiological findings of COVID-19 patients with "silent hypoxia," who had no dyspnea on admission even though their oximetry saturation was less than 94%. This retrospective cohort study included all COVID-19 patients (n = 270) at a large tertiary care hospital between January 31 and August 31, 2020. Clinical and radiological characteristics of patients who met our criteria of "silent hypoxia", which included those who reported no dyspnea even though oximetry saturation was <94%, were extracted. Eight patients (3.0%) met the criteria for "silent hypoxia." The median age was 61 years (interquartile range [IQR]: 48.8-72.3), and five (62.5%) were men. All patients had consolidation on CT and showed a moderate to high COVID-19 CT severity score (median: 13.5, IQR: 10.8-15.3). The median FIO2 of the maximum oxygen required was 55 (IQR: 28-70)%. Two patients (25.0%) were intubated, and one patient (12.5%) underwent extracorporeal membrane oxygenation. Some COVID-19 patients with "silent hypoxia" may develop severe disease. Close and accurate monitoring of patients using arterial blood gas and pulse oximetry is necessary, regardless of their symptoms.

Remote home monitoring (virtual wards) for confirmed or suspected COVID-19 patients: a rapid systematic review.

BACKGROUND: the aim of this review was to analyze the implementation and impact of remote home monitoring models (virtual wards) for confirmed or suspected COVID-19 patients, identifying their main components, processes of implementation, target patient populations, impact on outcomes, costs and lessons learnt. METHODS: we carried out a rapid systematic review on models led by primary and secondary care across seven countries (US, Australia, Canada, The Netherlands, Ireland, China, UK). The main outcomes included in the review were: impact of remote home monitoring on virtual length of stay, escalation, emergency department attendance/reattendance, admission/readmission and mortality. The search was updated on February 2021. We used the PRISMA statement and the review was registered on PROSPERO (CRD: 42020202888). FINDINGS: the review included 27 articles. The aim of the models was to maintain patients safe in the appropriate setting. Most models were led by secondary care and confirmation of COVID-19 was not required (in most cases). Monitoring was carried via online platforms, paper-based systems with telephone calls or (less frequently) through wearable sensors. Models based on phone calls were considered more inclusive. Patient/career training was identified as a determining factor of success. We could not reach substantive conclusions regarding patient safety and the identification of early deterioration due to lack of standardized reporting and missing data. Economic analysis was not reported for most of the models and did not go beyond reporting resources used and the amount spent per patient monitored. INTERPRETATION: future research should focus on staff and patient experiences of care and inequalities in patients' access to care. Attention needs to be paid to the cost-effectiveness of the models and their sustainability, evaluation of their impact on patient outcomes by using comparators, and the use of risk-stratification tools.

Silent hypoxia in COVID-19: pathomechanism and possible management strategy.

The novel coronavirus disease 2019 (COVID-19) has become a severe health issue, especially to the patients who develop silent hypoxia condition after SARS-CoV-2 infection. Due to the lack of dyspnoea and extremely low oxygen saturation level, these patients are at exceptionally higher risk. Although the prevalence of silent hypoxia in COVID-19 patients has been evident in several cases, the underlying pathomechanism behind this condition is still unclear. Silent hypoxia in SARS-CoV-2 infected patients can be diagnosed with the help of a pulse oximeter, blood gas levels, and a 6-min walking test. While the clinicians and researchers figure out the exact reason for this phenomenon, the patients must be under strict day-to-day monitoring. In this article, we aim to provide comprehensive insights into the underlying symptoms, mechanism, and possible factors behind the occurrence of silent hypoxia among COVID-19 patients.

Direct and indirect evidence of efficacy and safety of rapid exercise tests for exertional desaturation in Covid-19: a rapid systematic review.

BACKGROUND: Even when resting pulse oximetry is normal in the patient with acute Covid-19, hypoxia can manifest on exertion. We summarise the literature on the performance of different rapid tests for exertional desaturation and draw on this evidence base to provide guidance in the context of acute Covid-19. MAIN RESEARCH QUESTIONS: 1. What exercise tests have been used to assess exertional hypoxia at home or in an ambulatory setting in the context of Covid-19 and to what extent have they been validated? 2. What exercise tests have been used to assess exertional hypoxia in other lung conditions, to what extent have they been validated and what is the applicability of these studies to acute Covid-19? METHOD: AMED, CINAHL, EMBASE MEDLINE, Cochrane and PubMed using LitCovid, Scholar and Google databases were searched to September 2020. Studies where participants had Covid-19 or another lung disease and underwent any form of exercise test which was compared to a reference standard were eligible. Risk of bias was assessed using QUADAS 2. A protocol for the review was published on the Medrxiv database. RESULTS: Of 47 relevant papers, 15 were empirical studies, of which 11 described an attempt to validate one or more exercise desaturation tests in lung diseases other than Covid-19. In all but one of these, methodological quality was poor or impossible to fully assess. None had been designed as a formal validation study (most used simple tests of correlation). Only one validation study (comparing a 1-min sit-to-stand test [1MSTST] with reference to the 6-min walk test [6MWT] in 107 patients with interstitial lung disease) contained sufficient raw data for us to calculate the sensitivity (88%), specificity (81%) and positive and negative predictive value (79% and 89% respectively) of the 1MSTST. The other 4 empirical studies included two predictive studies on patients with Covid-19, and two on HIV-positive patients with suspected pneumocystis pneumonia. We found no studies on the 40-step walk test (a less demanding test that is widely used in clinical practice to assess Covid-19 patients). Heterogeneity of study design precluded meta-analysis. DISCUSSION: Exertional desaturation tests have not yet been validated in patients with (or suspected of having) Covid-19. A stronger evidence base exists for the diagnostic accuracy of the 1MSTST in chronic long-term pulmonary disease; the relative intensity of this test may raise safety concerns in remote consultations or unstable patients. The less strenuous 40-step walk test should be urgently evaluated.

Caution against precaution: A case report on silent hypoxia in COVID-19.

INTRODUCTION: Silent hypoxia is an entity that has been described in patients diagnosed with COVID-19. It is typically described as objective hypoxia in the absence of proportional respiratory distress. The physiological basis for this phenomenon is controversial, and its prognostic value is unclear. We present a case below, of a 66-year-old female presenting with severe hypoxia that was managed without mechanical ventilation. PRESENTATION OF CASE: A 66 year old female with multiple comorbidities initially presented with a cough, fever and an oxygen saturation of 70% on room air in the absence of respiratory distress or altered mentation. She subsequently tested positive for COVID-19 and was admitted to the intensive care unit; received oxygen via high flow nasal cannula and continuous positive pressure mask. The patient remained in the intensive care unit for 40 days under close observation and exhibited multiple episodes of silent hypoxia on weaning oxygen. She was discharged on room air with an oxygen saturation >90% after 56 days. The patient was not intubated during her stay. DISCUSSION AND CONCLUSION: Clinicians face a clinical dilemma on whether to intubate a "silently hypoxemic" patient, who displays hypoxia out of proportion to clinical examination. The decision is confounded by a lack of clear evidence on whether the benefits of precautionary intubation outweighs the risks, especially in the current COVID-19 pandemic. A recent paradigm shift that recommends delaying intubation further displays the need for clearer analysis of the situation. Our case demonstrates a favorable outcome of the latter approach, yet emphasizes a case-by-case approach until clearer recommendations are available.

COVID's Razor: RAS Imbalance, the Common Denominator Across Disparate, Unexpected Aspects of COVID-19.

A modern iteration of Occam's Razor posits that "the simplest explanation is usually correct." Coronavirus Disease 2019 involves widespread organ damage and uneven mortality demographics, deemed unexpected from what was originally thought to be "a straightforward respiratory virus." The simplest explanation is that both the expected and unexpected aspects of COVID-19 share a common mechanism. Silent hypoxia, atypical acute respiratory distress syndrome (ARDS), stroke, olfactory loss, myocarditis, and increased mortality rates in the elderly, in men, in African-Americans, and in patients with obesity, diabetes, and cancer-all bear the fingerprints of the renin-angiotensin system (RAS) imbalance, suggesting that RAS is the common culprit. This article examines what RAS is and how it works, then from that baseline, the article presents the evidence suggesting RAS involvement in the disparate manifestations of COVID-19. Understanding the deeper workings of RAS helps one make sense of severe COVID-19. In addition, recognizing the role of RAS imbalance suggests potential routes to mitigate COVID-19 severity.