Relationship Between Arterial-Alveolar Oxygen Gradient, Mortality and Admission to Intensive Care Unit in Severe Covid-19 Related Pneumonia: A Pilot Study

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV-
2) is the causative agent of the respiratory disease later named
Coronavirus Disease 2019 (COVID-19), remaining a world public
health emergency at present...

Combination of different risk factors into prognostic models led researchers to identify and validate some nomograms or calculation tools, apparently endowed with a good performance (area under the curve, AUC > 0.8 in all trials) [3][4][5][6].Although pneumonia-associated hypoxemia is the main complication causing hospital admission in COVID-19 patients, none of these studies considered the impact of ABG parameters, and in particular of the alveolar-arterial gradient. In a really interesting editorial entitled

"Basing Respiratory Management of COVID-19 on Physiological
Principles", [7] Tobin underlined the importance of calculating the alveolar-arterial oxygen (A-a O2) gradient, since it is able to assess the pathophysiological basis of the hypoxemia more precisely than the commonly used ratio PaO2/FiO2. In fact, PaO2/FiO2 may have minor accuracy, because it is influenced by changes in two parameters (PaO2 and/or FiO2) [7]. Consistent with this proposal, we decided to assess if the calculation of A-aO2 upon arrival in the emergency room is a predictive factor of two principal outcomes in patients with COVID-19 pneumonia: 1) Mortality, 2) Early (within 24 hours) admission to Intensive Care Unit (ICU).

Methods
We retrospectively reviewed the medical records of consecutive patients with laboratory-confirmed infection by SARS-CoV2 admitted to the Gemelli Hospital of Rome, Italy, from 1 March to 1 May 2020, and finally classified as critical cases (admission to ICU).     Table 3: Differences between the group of patients early admitted to ICU (within 24 hours since arrival at emergency room) and the group of those admitted later concerning the principal parameters of arterial blood gas analysis assessed in ambient air upon arrival in the ED.

Discussion
The AaDO2 is the measure of the difference between the oxygen concentration in the alveoli and in the arterial system [7]. It has a fundamental clinical utility as it helps to evaluate if hypoxemia is due to dysfunction of the alveolar-capillary unit ("lung" failure, increased A-a O2 gradient) or to a "pump" failure (normal A-a O2 gradient). Hypoxemia with COVID-19 is generally associated with an increased alveolar-to-arterial oxygen gradient, due to either ventilation-perfusion mismatch or intrapulmonary shunt, linked to a (variable) inflammatory involvement of pulmonary parenchyma [8]. It could be hypothesized that, in patients with COVID-19 pneumonia, the higher the gradient, the more severe the lung inflammatory damage and then higher the risk of death. This hypothesis has been already proven in patients with community acquired pneumonia (CAP) [9,10]. In a recently published study, with mortality, both with the problem of arterial hypertension and its treatment with ACE-i/ARB, which have been postulated to play a role in the pathogenesis of SARS-CoV2 infection [12][13][14].
Interestingly, the group with poor prognosis showed at arrival significantly lower values of systolic and a trend toward lower diastolic blood pressure and higher lactate and CRP levels, as if these patients were heading towards ahemodynamic impairment.
These abnormalities look like first signs of an incipient 'viral sepsis' or 'cytokines storm', typical of more severe and often mortal COVID-19 cases [15,16]. In conclusion, our preliminary study represents a hypothesis-generating paper. The alveolar-to-arterial gradient and its difference seemed useful to well stratify patients at risk of early precipitation of respiratory failure but were not related to mortality. Further, possibly prospective, studies on a larger population are needed to confirm the present findings.

Conflicts of Interest
We have no conflict of interests to disclose and the manuscript has been read and approved by all named authors.