DISCUSSION:
To our knowledge this is the first study demonstrating the incidence and outcome of new onset atrial fibrillation in patients with severe COVID-19 treated in ICU. There is increased evidence that the systemic inflammatory response per se is a predominant trigger of NOAF in critically ill patients [13]. In the literatures available on cardiovascular complications related to critically ill patients with COVID-19, the nature and classification of the arrhythmogenic events and their mechanisms have not yet well described. Our retrospective multicentre study assessing NOAF, showed an incidence of 14.6% amongst patients with COVID-19 treated in ICU and this is comparatively lower than the occurrence of NOAF reported in studies relating to severe sepsis in ICU in general [9-11]. This raises the question of whether the mechanism triggering AF in COVID-19 differ from other forms of sepsis despite high systemic inflammatory milieu by pro-inflammatory cytokine storm and possible direct viral invasion into cardiomyocytes through angiotensin-converting enzyme 2 (ACE2) receptors [15].
A systematic review by Kuipers et al, described that advanced age, male gender, obesity, organ failure were associated with development of AF during sepsis. In contrast to reported associations in the general population, diabetes and hypertension were not identified as risk factors in sepsis [16,17]. In our study advanced age, chronic heart failure and chronic kidney disease have shown to be a risk factor for development of NOAF among severely ill patients with COVID-19. Presence of diabetes, obesity or hypertension has not been identified as trigger for NOAF in our cohort (Table 1).
Patients with and without NOAF did not have any significant difference in the trend of inflammatory markers or troponin, however AKI was a risk for NOAF in patient with severe form of COVID-19 infection.
Just over 90% of our study population showed raised troponin T level above the normal range, but there was no significant association with NOAF or indeed left ventricular systolic function. Further detailed studies with cardiac MRI may help to assess the degree of myocardial involvement through tissue characteristics. There is compelling evidence that LA size is an independent predictor for atrial fibrillation in general population [18-20] and likewise in our cohort with severe COVID-19, enlarged LA size certainly remained a risk factor for NOAF.
Uncontrolled activation of coagulation cascade following lung injury contributes to lung inflammation in ARDS [21]. In general, significantly higher D-Dimer levels are found in patients with severe pneumonia/ARDS and also shown to be a predictor of poor clinical outcome and mortality [22]. COVID-19 data from recent studies described similar findings [14, 23] and our data reveal very high levels of D-Dimer in our cohort with more than one-third having levels >50mg/L. This indicates the severity of COVID-19 infection and the thrombosis risk in our study population, however did not achieve statistical significance when considering the in-hospital death.
The manifestation of even a single episode of AF is associated with increased mortality and poor outcome in critically ill patients with sepsis [10,11,16]. In this study the occurrence of NOAF was strongly associated with poor outcome. Patients who develop NOAF earlier during the course of COVID-19 illness had worse outcome and this may be a useful marker for physicians to predict prognosis.
Patients with severe sepsis who developed NOAF have a greater risk of in-hospital stroke than patients with pre-existing AF or individuals without history of AF [15,24]. We have reported one case of ischaemic stroke amongst the group developed NOAF with poor outcome. However, it was difficult to ascertain the contribution by AF, as COVID-19 infection per se has risk of arterial thromboembolism due to hypercoagulable state.
Anticoagulation significantly reduces the risk of stroke amongst patients with high risk factors, based on CHA2DS2 VASc score (congestive heart failure, hypertension, age, diabetes mellitus, stroke, vascular disease and sex). However there is not much evidence to support anticoagulating critically ill patients in ICU which may expose them to risk of bleeding during sepsis [25,26] or invasive intensive care management. Virally driven hyper-inflammation with cytokine release will lead to hypercoagulable state and propensity for disseminated intravascular coagulation (DIC) in severe COVID-19 [27]. This is increasingly evident as substantial proportion of patients develop venous and arterial thromboembolic complications which was seen in our cohort. This may in turn could increase the risk of stroke in patients who develop NOAF with severe COVID-19, and careful assessment regarding decision on anticoagulation is warranted in these patients irrespective of CHA2DS2 VASc score. However further studies are needed to determine the value of anticoagulation in treating NOAF in severe COVID-19 patients.