COVID-19-induced-APS-likesyndrome is a new term [12], as many studies reported a priori autoantibody production in severe-COVID-19 patients (13),15]. Their prevalence is balanced among studies. A prospective observational study performed at a third level hospital in Madrid, revealed that only 8.3% of the patients were positive for anticardiolipin IgM and anti-β2-glycoprotein-I IgM [16]. On the contrary, Zuo et al. found that 52% of their patients tested positive for aPLA [17].
Until now, the incrimination of aPLA in the coagulopathy linked to COVID-19 still controversial. These autoantibodies may occur in critically ill patients following different infections, such as sepsis [2, 18].
In our study, we enrolled 43 critically ill COVID-19 patients and 31 critically ill non-covid19 patients with pulmonary origin sepsis, admitted in the intensive care unit in the military hospital of Tunis between October 2020 and May 2021. All patients were matched by age, sex, and comorbidities (p > 0.05).
We found a slightly significant higher rate of mortality in COVID-19 patients (79%) compared to septic non-COVID-19 patients (54.83%) (p = 0.026).
The SOFA-score was calculated among the groups to evaluate quantitatively and objectively the degree of organ failure through several parameters including the oxygenation efficiency, mean arterial pressure, creatinine or urine volume, bilirubin, platelets and Glasgow Coma Scale (GCS) for the respiratory, circulatory, renal, hepatogenic, coagulation and neurologic systems, respectively [11]. Prospective evaluations have validated the SOFA score as a usefull tool for the assessment of morbidity in critical illness [19].
The current study showed that the SOFA-score was dramatically higher in the COVID-19 patients group (8.44 ± 2.87) than in non-COVID-19 patients group on day 1 (7.47 ± 2.61) (p = 0.005), day 3, day 5, day 8 and day10 (p < 0.0001), inferring aggravating conditions in the COVID-19 patients. Indeed, Sijia Liu et al. reported that a SOFA-score ≥ 3 is associated with mortality in critically ill COVID19 patients. This score is a highly sensitive marker of in-hospital mortality [20].
In respiratory infections, hypoxic conditions are typical due to decreased oxygen inhalation [21]. Indeed, we observed severe respiratory dysfunction measured using the SOFA-respiratory component between the two groups on the admission day, day 3, day 5, day 8 and day 10. Assessment of the respiratory SOFA-component relies on invasive arterial monitoring to measure arterial partial pressure of oxygen followed by calculation of the PaO2/FiO2 ratio which refers to the oxygenation index and leads to SOFA score variation [22]. The specific SOFA score ranges from 0 to 4. This score was significantly higher in COVID-19 (≥ 2) on day 1 (p = 0.001) to day 10 (p < 0.0001), than in non COVID-19 patients (< 2).
Furthermore, its evolution among time was significantly decreased in non-COVID-19 pulmonary origin sepsis patients (p < 0.0001) between day 1 (1.29 ± 1.16) and day 10 (0.41 ± 0.71). Conversely, the evolution of respiratory SOFA-component in COVID-19 kept high levels between day 1 (2.6 ± 1.66) and day 10 (2.93 ± 1.38), and no decrease has been registered (p = 0.304).
This result indicates an exaggerated respiratory distress and lung injury in SARS-CoV2-viral pneumonia patients compared to bacterial pneumonia in non-COVID-19 septic patients.
Different studies have shown that SARS-CoV-2 infection induces down-regulation of surfactant proteins and an increase in cell death [23]. SARS-CoV-2 infects alveolar epithelial cells by recognizing the ACE2 receptor [24]. Following the virus internalization, the exfoliation of ACE2 reduces the expression of ACE2 on the cell membrane which weakens its lung-protective effects [25, 26]. This may lead to alveolar epithelial cell necrosis and aggravation of lung inflammation [26].
In our study, we measured aCLIgMGA and aPSIgMGA autoantibodies in critically ill COVID-19 and non-COVID-19 patients, at different time points during their hospitalization in ICU.
We found 58.1% of COVID-19 patients were positive for at least one antibody based on the manufacturer’s cutoff. A striking difference was observed between the autoantibody profiles in COVID-19 patients as compared to the one in non-COVID-19 concerning the titers of aPLA. The vast majority of positive results were aCL IgMGA (58.13% COVID-19 vs 16.98% non COVID-19), rather than aPS IgMGA (23.25% covid-19 vs 7.5% non-COVID-19).
This high occurrence of aPLA autoantibodies in patients with COVID-19 could be explained by the high risk for thromboembolic events. Indeed, Hui Shi et al. described the endothelial cell activation as a part of the COVID-19 thrombo-inflammatory storm. They reported that circulating aPLA may be predictors of endothelial cell activation in COVID-19 and their depletion restrained the upregulation of E-Selectin, VCAM-1 and ICAM-1, the three markers of endothelial cell activation [28].
Interestingly, we detected modest correlations between anticardiolipin, anti-PS autoantibodies and the respiratory SOFA component of the same day of measurement for both groups. We noted that the correlation was slightly stronger, at day 8 (r = 0.634, p < 0.0001; r = 0.633, p < 0.0001), in the COVID-19 group. This may suggest a local production of aPLA in lungs.
Moreover, the respiratory-SOFA component on day 5 was strongly and significantly correlated to aPLA titers on day 8 and 10 for both groups. This led us to think that the respiratory SOFA-component can predict the increase in the anticardiolipin and antiphosphatidylserine antibodies.
In the context of major cellular distress and tissue injury, the system may be overwhelmed and mitochondrial Damage-Associated Molecular Pattern molecules (DAMPs) are released into the cytoplasm [28], triggering a pro-inflammatory response. This led us to think about a production of anti-phospholipid antibodies against cardiolipin located in the internal membrane of mitochondria [29], which escaped the autophagy due to a dysregulated immune response [30].
To summarize, our study clarifies, at least in part, the kinetics of aPLA synthesis in COVID-19 and in pulmonary sepsis and supports the use of aPLA autoantibodies as predictors of a potential harmful increase in the respiratory SOFA component. The aPLA assays had a good prognostic efficiency, suggesting that measuring aCL and aPS might be used as a secondary criterion for determining severity.