In the current study, we report the clinical characteristics of a cohort of critically ill patients with COVID-19 that were admitted to the RICU of a national reference center for respiratory diseases in Mexico City. Our analyses showed that most demographic, clinical, radiological, and biochemical characteristics of Mexican patients with severe SARS-CoV-2 infection resemble those reported previously by other groups from China, Europe, and the United States. Furthermore, we determined which factors were independently associated with mortality using a non-conventional statistical approach that included machine-learning algorithms and traditional regression analyses. This strategy of analysis allowed us to identify six variables that had the highest impact on the mortality of our cohort: fold change in VR, fold change in lymphocyte counts, AKIN, uric acid, LDH, and PaO2/FiO2. From these, fold change in lymphocytes and PaO2/FiO2 at admission acted as independent protective factors.
A dramatic depletion of total lymphocytes, as well as of CD8 + and CD4 + T-cells, has been reported in patients with SARS-CoV-2 infection [24–26]. This phenomenon is the expression of a dysregulated immune response elicited by the virus that favors immunosuppression and is associated with a high risk of secondary bacterial infection, septic shock, and organ dysfunction . Indeed, lymphopenia has been described as a marker of severity and a predictor of mortality in COVID-19 . In our cohort, baseline lymphocyte counts were extremely low in all patients, with no differences between survivors and non-survivors. These data may indicate that despite lymphopenia is a readout of severity in the overall population of COVID-19 patients, this marker is not further informative when used only among critically ill individuals. Thus, lymphocyte counts on admission should be used only in the decision-making for patients with mild-to-moderate forms of the disease to predict the progression to severe COVID-19.
Recovery of the adaptive immune system with an increase in the number of circulating T lymphocytes is necessary to eliminate the virus . Notably, we also found that longitudinal increases in the number of circulating lymphocytes here expressed as a fold change in lymphocytes (defined as the ratio of the difference between lymphocyte counts at discharge/death and values at admission divided by the initial counts), have a strong protective effect against mortality. In other words, a longitudinal increase in lymphocytes associates with a decreased mortality risk, while a decrease in lymphocytes correlates with a significant increase in the risk of death. This result is consistent with the rapid and dramatic restoration of peripheral T lymphocytes observed in patients who recovered from SARS-CoV-2 infection . Hence, our results indicate that changes in the lymphocyte counts could be used as a parameter to guide therapeutic decisions for critically ill COVID-19 patients. For instance, this parameter could determine which patients would benefit from the use of steroids. These drugs could have both favorable and unfavorable consequences. For example, in patients with an exaggerated inflammatory response, steroids may reduce organ damage. In contrast, in patients with severe immunosuppression, steroids could accentuate this defect, increasing the risk of sepsis and mortality; applying treatments that stimulate the immune system could be useful in these patients .
VR is governed by the production of carbon dioxide (CO2) and the ventilatory efficiency (1-(Vd/Ve)) and can be easily calculated at the patient's bedside using ventilation and blood gas parameters. It correlates with the percentage of dead space and is also associated with an increased risk of mortality [31–33]. Previous studies on patients with ARDS and COVID-19 have reported a significant association between the VR at admission and mortality . In our patients, we did not observe this association upon admission to the RICU. However, we observed that a longitudinal increase in VR was a marker of poor clinical outcome in our cohort of patients with ARDS due to COVID-19. This result is consistent with other reports that demonstrated that an increase in the fraction of dead space during the first weeks of ARDS is an independent predictor of mortality [31–33]. In summary, the worsening of the VR in our cohort was independently associated with an increased risk of mortality. Similar to the tidal volume adjusted for the predicted weight, plateau pressure, DP, and PaO2/FiO2 ratio, the VR should be monitored daily and used to make adjustments to the ventilatory parameters, always taking into account the variables mentioned above.
The most striking mortality risk factor identified in our study population was the incidence of AKIN. The injury of the kidney has been widely reported in patients with sepsis and severe ARDS associated with other respiratory pathogens, such as influenza viruses [35–37]. Indeed, AKIN is a well-recognized mortality risk factor in patients with severe pneumonia caused by the pandemic influenza A(H1N1)pdm09 virus . Similarly, a high incidence of AKIN has been reported in patients with COVID-19. For instance, Hirsch et al. reported an incidence of 36.6% in a cohort of 5449 patients with COVID-19 . However, in patients with respiratory failure who required invasive MV, the incidence of AKIN was 89.7%, and in those who required hemodialysis the mortality was 55% . In our cohort, up to 65% of the patients developed AKIN, and its incidence had a strong effect on mortality. Several mechanisms could contribute to the de velopment of AKIN among patients with severe COVID-19, including direct injury driven by the virus and detrimental effects of the high levels of circulating proinflammatory mediators, endothelial dysfunction, and micro-thrombosis of renal blood vessels. Independently of the causative mechanism, the application of preventive or therapeutic measures (implementation of the KDIGO supportive care guidelines ) to avoid AKIN or to prevent progression to more advanced stages must be a priority in critically ill patients with COVID-19.
Uric acid, LDH, and PaO2/FiO2 also impacted on mortality of our study population. Interestingly, little evidence exists about the prognostic value of uric acid in COVID-19. Hence, ours is among the first studies that bring forward this marker for mortality prediction after SARS-CoV-2 infection. As uric acid levels primarily depend on the balance between its production and excretion through the urine, we speculate that the elevated uric acid levels observed among critically ill COVID-19 that died are related to the high incidence of renal dysfunction in these individuals. Notably, other biomarkers of renal function, such as Cr, were not associated with mortality. Collectively, these data indicate that uric acid may be a more useful readout of the renal function status than Cr and blood ureic nitrogen (BUN) among patients with COVID-19 in critical conditions. Regarding LDH, several studies have reported that this is a good marker to predict mortality in patients infected with SARS-CoV-2 [40, 41]. Hence, our study reinforces the usage of LDH as a prognostic indicator of mortality that could be useful to guide therapeutic interventions.
Finally, the PaO2/FiO2 ratio showed a significant protective effect against mortality in our analyses. The PaO2/FiO2 ratio is a crucial determinant of the severity of ARDS, according to the Berlin definition . The majority of our patients showed ground-glass opacities on chest tomography, without extensive consolidation images. This explains the rapid response of many patients to oxygen administration and the poor response at this stage to recruitment maneuvers because there are no extensive recruitable consolidation areas. Therefore, the primary mechanism of hypoxemia in these patients in the initial phase is an abnormality in the distribution between ventilation and blood flow; the latter is assumed to be abnormal due to endothelial and vascular alterations documented among COVID-19 patients . Therefore, the PaO2/FiO2 ratio may be a good physiological biomarker of the amount of pulmonary shunt and lung parenchymal damage in the early phase of ARDS due to COVID-19, which explains why this parameter was a protective factor against mortality in our study. In contrast with our results, other investigations have shown that the PaO2/FiO2 ratio is not a strong predictor of mortality, which may be related to the clinical heterogeneity observed in studies involving patients with moderate-to-severe COVID-19.
One limitation of the study is the small size of the cohort, which originated from a single third-level center in Mexico City. Therefore, although our results are consistent with those reported in China, Europe, and North America, and despite the machine-learning approach used in our study may compensate for this caveat, the predictive value of the mortality risk factors identified here require further external validations in larger cohorts.