In response to: preventing atrial fibrillation in COVID-19: exploring the role of interleukin-6 receptor antagonists

KEYWORDS:

• COVID-19
• new-onset atrial fibrillation
• Tocilizumab
• C2HEST score
• IL-6 receptor antagonists

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Preventing atrial fibrillation in COVID-19: exploring the role of interleukin-6 receptor antagonists

We have read the Letter to the Editor about ‘Preventing Atrial Fibrillation in COVID-19: Exploring the Role of Interleukin-6 Receptor Antagonists.’ In this article, the author has described the role of Interleukin-6 (IL-6) in the pathophysiology of COVID-19 pneumonia, and the role of IL-6 receptor antagonists (Tocilizumab) in reducing all-cause mortality. Furthermore, the author has reviewed the role of IL-6 in new-onset atrial fibrillation in the general population and also the role of Tocilizumab in reducing new-onset atrial fibrillation in COVID-19. Based on these observations, the author has proposed the validation of the C2HEST score among COVID-19 patients and its use to identify the patients at risk of new-onset atrial fibrillation. This identification and use of IL-6 receptor antagonists in patients with high C2HEST scores can prevent atrial fibrillation among COVID-19 patients and reduce in-hospital mortality.

The majority of the atrial arrhythmias in COVID-19 patients were observed in the patients who were admitted to the intensive care unit, were on a ventilator (invasive or noninvasive), and were terminally ill and with moderate/severe COVID-19 illness [1–4]. Different pathophysiological mechanisms are responsible for atrial arrhythmias in COVID-19 patients. It includes hypoxia, cytokine storm, IL-6 mediated atrial fibrosis and deranged calcium handling in atrial myocytes, hypoxia-mediated myocardial injury, electrolytes imbalance, multiorgan dysfunction, direct virus-induced myocardial injury, myocardial stretch, use of inotropes, and underlying comorbidities [1–4].

Recently, Tocilizumab has been approved by the U.S.A. FDA in hospitalized COVID-19 patients who are receiving systemic corticosteroids and are on supplemental oxygen, invasive ventilator, or extracorporeal oxygen support. Tocilizumab reduces systemic inflammation/cytokine storm, use of supplemental oxygen and invasive/noninvasive ventilator, and death in COVID-19 patients, as observed in different studies [5,6].

Recently Menchaca et al. observed a significant reduction in cardiac arrhythmias in severe COVID-19 patients who were on invasive or noninvasive ventilators with Tocilizumab therapy [7]. In contrast to this, Patel et al. in an Umbrella review, failed to observe a significant difference in new-onset atrial fibrillation among severe COVID-19 patients who were on Tocilizumab therapy. However, they observed a significant reduction in total mortality with Tocilizumab therapy. Patel et al. have proposed low-quality studies as a reason for this observation [8].

Tocilizumab has been used in patients with Rheumatoid arthritis, Giant cell arteritis, and Juvenile rheumatoid arthritis for a long time. However, no real-world data is available that suggests that it reduces the incidence of atrial fibrillation in these subsets of patients with elevated serum IL-6 levels. Also, Tocilizumab was never studied in the past for the treatment of atrial fibrillation despite the available evidence of elevated levels of IL-6 in atrial fibrillation patients.

We think, the reduced incidence of atrial fibrillation with Tocilizumab in COVID-19 patients was not due to the blockage of IL-6 effect on atrial tissue including atrial fibrosis [4] and abnormal calcium handling but mainly due to its indirect mechanism including reduced acute respiratory distress syndrome (ARDS) severity, reduced oxygen requirement, improved tissue oxygenation, less myocardial injury (Hypoxia-induced type II myocardial injury), and reduced incidence of multiorgan dysfunction, which in turn reduce the severity of COVID-19 illness [9]. This mechanism can explain why Tocilizumab reduces both the incidence of atrial fibrillation and mortality in moderate to severely ill COVID-19 patients who are hypoxic, but not in patients without any COVID-19 illness and hypoxia in the general population (Rheumatoid arthritis, Giant cell arteritis, and Juvenile rheumatoid arthritis). Similarly, Amiodarone, the drug used and recommended for the treatment of atrial arrhythmias in COVID-19 patients [4], was associated with high mortality in COVID-19 patients who were on amiodarone before hospitalization and during hospitalization [10]. It could be because Amiodarone has no lung protective effect as it can lead to acute lung toxicity/fibrosis.

From the above observation, we think any beneficial effect seen with Tocilizumab on atrial fibrillation and mortality reduction in future COVID-19 trials will be due to its anti-inflammatory action on the lungs rather than a dual mode of action as proposed by the author. To understand the role of Tocilizumab as an antiarrhythmic it will be much better to study the incidence of atrial fibrillation in general population patients who are already on Tocilizumab therapy without any lung pathology.

Mountantonakis et al. have observed an association of new-onset atrial fibrillation in COVID-19 patients with in-hospital mortality [2]. In contrast, Rosenblatt et al. in a multicentre study found no association between a new-onset atrial fibrillation and in-hospital mortality among COVID-19 patients. The atrial fibrillation was the marker of terminal illness in that study [2]. The above observation suggests that any interventions/therapy directed only to reduce the incidence of atrial fibrillation rather than underlying lung pathology (ARDS) among COVID-19 patients may not reduce the mortality in COVID-19 patients.

The author has proposed a C2HEST score to determine the risk of atrial fibrillation for our study population. However, the mean age of the study population, the patients with mild/moderate illness, and severe illness in our study were equal to or less than 60 years. Also, none of the study patients had a history of hyperthyroidism [1]. In the C2HEST score, no point is given to diabetes mellitus, an important risk factor for atrial fibrillation and COVID-19 illness and its complications (use of supplemental oxygen, invasive or noninvasive ventilator, and admission to an ICU) [11].

The underlying pathophysiology of atrial fibrillation in critically ill patients is different from community atrial fibrillation [12,13]. C2HEST score is validated for community atrial fibrillation, not for atrial fibrillation occurring in critical illness. Also, in the C2HEST score, no points are given to oxygen requirement, use of ventilator (invasive/noninvasive), COVID-19 illness severity, systemic oxygen saturation (SpO2), PO2/FiO2 ratio, admission to an intensive care unit, myocardial stress and injury (Elevated cardiac troponin and N-terminal pro – B-type natriuretic peptide), markers of inflammation, and multiorgan dysfunction, important risk factors for atrial fibrillation in critically ill COVID-19 patients [1–4]. Hence, the C2HEST score may not be appropriate to determine the risk of atrial fibrillation in critically ill COVID-19 patients.

However, we think a modified C2HEST score with the inclusion of the above-mentioned factors would be more appropriate in critically ill COVID-19 patients. The SAFE Score proposed by Klein Klouwenberg et al. is one such score that was used to determine the risk of new-onset atrial fibrillation in critically ill sepsis patients. This score includes factors like obesity, time since admission, serum potassium level, renal failure, age, elevated inflammatory markers, immunocompromised status, shock, and FiO2 [14].

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Acknowledgement

We acknowledge the role of Sudheesh Kumar Kattumannil (Indian Statistical Institute, Chennai, India), Dr. Khushboo Srivastav (Department of Ophthalmology, Shubh Netram, Nirman Vihar, New Delhi, India), Siya Gupta, Dr. Monica Sharma (Consultant & associate professor, Department of Hematology), Sonali, Ram Niwas (Lab technicians, Department of Hematology), Yash Kumar, Uday Kumar, Nikhil, and Himani Arora, in conducting this study.

Additional information

Funding

This paper was not funded.