Asymptomatic severe hypoxemia (reduced pO₂(a)) is an important feature of COVID-19 for some patients; mechanisms discussed and prognosis examined

Coronavirus disease 2019 (COVID-19) is the potentially fatal respiratory disease caused by infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has spread worldwide from its origin in Wuhan, China since December 2019. In the absence of a protective vaccine the COVID-19 pandemic continues to grow; by the end of November 2020, 63 million cases (tested positive for SARS-CoV-2) had been recorded worldwide and the best estimate global death toll due to COVID-19 stood at 1.5 million.

Although potentially fatal, COVID-19 is a mild, self-limiting disease for the vast majority. Around 80% of SARS-CoV-2 infected individuals - although potentially contagious during the approximate 5-14 day period following exposure to the virus - suffer either no symptoms at all, or mild, non-specific ‘flu like’ symptoms (most commonly: fever, cough, malaise, aches and pains) that usually resolve with little or no medical intervention.

For the remaining approximate 20% of infected individuals, who are phenotypically and/or genetically predisposed, COVID-19 is more serious, with infection of the lower respiratory tract leading to pneumonia and consequent breathing difficulties requiring hospital admission. Those most severely affected with pneumonia develop acute respiratory failure and acute respiratory distress syndrome (ARDS) requiring admission to intensive care. COVID-19 can progress from the lungs to cause systemic conditions mediated by, or associated with hyper-inflammation/cytokine storm, such as sepsis, disordered coagulation (hypercoagulability) and ultimately, multi-organ failure. Between 20-30% of COVID-19 patients whose severe condition warrants admission to intensive care do not survive to discharge. During the first months of the pandemic before current evidenced based treatment regimens had emerged, intensive care mortality was significantly higher: of the order 50-60%.

As a primarily infective respiratory disease that threatens the principal, life preserving function of the lungs: alveolar gas exchange, COVID-19 is associated with risk of reduced blood oxygenation (hypoxemia) and consequent life threatening tissue hypoxia if cardiac compensation for hypoxemia is insufficient/impaired. Hypoxemia is evidenced by arterial blood gas analysis as reduced partial pressure of oxygen (pO₂(a)) and reduced oxygen saturation (sO₂(a)). In health, pO₂(a) is maintained within the range 80-100 mmHg (10.6-13.3 kPa), and sO₂(a) is maintained between 95% and 100%.

Pulse oximetry provides the means for estimating sO₂(a) non-invasively ie without recourse to arterial blood sampling. The finger probe pulse oximeter records SpO₂. With some important provisos, SpO₂ is a clinically acceptable measure of the gold standard oxygen saturation parameter, sO₂(a) and therefore a valid and very convenient means of identifying hypoxemia.

Hypoxemia is diagnosed if pO₂(a) is less than 80 mmHg (10.6 kPa) and/or sO₂(a) /SpO₂ is less than 95%:

• Mild hypoxemia:
  pO₂(a) 79-70 mmHg (10.5–9.3 kPa)
  sO₂(a) /SpO₂ 94-90%
• Moderate hypoxemia:
  pO₂(a) 69-60 mmHg (9.2- 8.0 kPa)
  sO₂(a) /SpO₂ 89-85%
• Severe hypoxemia:
  pO₂(a) 50-59 mmHg (6.6-7.8 kPa)
  sO₂(a) /SpO₂ 84-80%
• Extreme hypoxemia:
  pO₂(a) < 50 mmHg (6.6k Pa)
  sO₂(a) /SpO₂ < 80%

Severe/extreme hypoxemia is regarded a life-threatening condition principally because of reduced oxygen delivery to tissues and consequent high risk of hypoxic tissue damage.

Signs and symptoms of hypoxemia may include: breathlessness (dyspnea), laboured breathing involving accessory muscles of respiration, increased breathing rate (tachypnea), increased heart rate (tachycardia), headache and confusion.

Almost all patients admitted to hospital with COVID-19 have hypoxemia and require supplemental oxygen. The severity of hypoxemia in COVID-19 is independently associated with in-hospital mortality and so the finding of severe hypoxemia at admission is important in helping to identify those COVID-19 patients who have a poor prognosis and require transfer to the intensive care unit.

One of the features of hypoxemia among COVID-19 patients is that not infrequently it initially occurs without symptoms of respiratory distress. Clinicians have been puzzled by the observation that some COVID-19 patients present without any complaints of breathing difficulty, but arterial blood gas analysis and/or pulse oximetry reveals remarkably low blood oxygen levels, which in some cases are seemingly incompatible with life.

This apparently counterintuitive feature of COVID-19, that is severe hypoxemia without dyspnea, which has been dubbed ‘happy hypoxemia’ or less emotively and more accurately, ‘silent hypoxemia’, is the subject of these two highlighted recently published articles.

The first of the two articles, whose principal author is an eminent US academic respiratory/critical care physician, focusses on discussion of the possible mechanisms involved in ‘happy/silent’ hypoxemia.

By way of introduction, the authors present three very brief case reports to illustrate the phenomenon they seek to explain. All three patients are male (aged 64 yrs, 74 yrs and 58 yrs) and were diagnosed with COVID-19 following positive test for SARS-CoV-2. During delivery of supplemental oxygen treatment, the following pulse oximeter (SpO₂) and blood gas analyzer results (pO₂(a), pCO₂(a) and sO₂(a) were recorded:

Despite severe/extreme hypoxemia, on questioning all three patients repeatedly denied any difficulty breathing. They were all ‘comfortable’, not using any accessory muscles of respiration and performing normal tasks (drinking, using cell phone) without difficulty.

In summary, the authors argue that most, if not all cases of ‘silent/happy’ hypoxemia can be explained in terms of well-established pathophysiological mechanisms, although they do not discount the possibility that it may arise, at least in part, as a result of an as yet unidentified effect of possible SARS-CoV-2 binding- via ACE receptors - to pO₂(a) sensing cells of the respiratory centre in the brain.

They provide some detail of the physiological response to hypoxemia, including the sensing of reduced pO₂(a) by the respiratory centre in the brain with consequent increased ventilation. They also outline the mechanism of hypoxemia induced breathlessness and describe the relationships between increased ventilation, prevailing carbon dioxide tension (pCO₂(a)) and perception of breathlessness. In essence, for a given degree of hypoxemia induced increased ventilation, those with low pCO₂(a) are much less likely to experience breathlessness than those with high pCO₂(a).

Breathlessness is a subjective phenomenon and throughout the paper the authors emphasise the variability in perception of breathlessness among those with hypoxemia, citing studies in which healthy individuals have been rendered hypoxemic either from being at high altitude or by laboratory experimentation; some report breathlessness, some do not. The authors invoke the widely-recognised variability in pain perception to help convey this general point.

The authors identify and explain the mechanism of three factors that are likely to potentiate loss of breathlessness perception during hypoxemia ie predispose to silent/happy hypoxemia. These are: old age (> 65years), increased body temperature (fever), and a history of diabetes. Since fever is a very common presenting feature of COVID-19 and a disproportionate number of patients with severe COVID-19 are elderly and/or have diabetes, it would seem that COVID-19 induced hypoxemia is inherently more likely to occur without sensation of breathlessness than hypoxemia induced by other conditions.

In addition to the pathophysiological discussion, the authors also highlight the well documented limitation of pulse oximetry to accurately determine sO2(a) at low oxygen saturation; SpO₂ underestimates true sO₂(a) at low levels as reflected in each of the three case reports. The authors suggest that caregivers may be unaware of these limitations of pulse oximetry and consequently be left with a false impression that patients are suffering a more severe degree hypoxemia than is actually the case. The implication is that the authors believe some cases of silent hypoxemia diagnosed by pulse oximetry are simply cases of patients with a less severe degree of hypoxemia that would not necessarily be expected to be associated with breathlessness.

The limitations of pulse oximetry at low oxygen saturation and during any critical illness underlines the superiority of arterial blood gas analysis for accurate assessment of hypoxemia severity and by extension, accurate diagnosis of ‘happy/silent’ hypoxemia.

The second of the two highlighted papers is a report of a French retrospective study focussing on COVID-19 patients who on admission to hospital reported no breathing difficulty (no dyspnea). Results of the study provide insight into the frequency of ‘silent/happy’ hypoxemia and reveal a poor outcome for COVID-19 patients who present with ‘silent/happy’ hypoxemia.

The study population comprised 1712 COVID-19 patients (positive for SARS-CoV-2). On admission to hospital 1107 (64%) had no breathing difficulties. Of these 1107 patients without dyspnea, 757 (68.4%) had pneumonia (confirmed by computed tomography scan within 48 hrs of admission).

The results of arterial blood gases were available for a subset (n=161) of these patients without dyspnea, Close to a third (28%) had blood gas results (reduced pO₂(a) in combination with reduced pCO₂(a), which allowed a diagnosis of silent/happy hypoxemia.

Asymptomatic hypoxemia was associated with poor outcome; 33.3% were transferred to ICU and 25.9% died.

Clearly, dyspnea is a less common presenting symptom of severe COVID-19 disease than was once supposed. The absence of dyspnea in a COVID-19 positive patient should not be considered reassuring of well-being or used to exclude hypoxemia/hypoxia. In view of the poor outcome associated with asymptomatic hypoxemia revealed by this study, the term ‘happy’ hypoxemia as applied to COVID-19 patients is something of a misnomer.