In this study, prevalence of RB in patients with COVID-19 was 60.6%. This rate was higher than previous reports. Capoferri et al. reported 110 hospitalized COVID-19 patients in which 36% developed relative bradycardia and of the patients with a fever 56% developed relative bradycardia [4]. Our definition of a relative bradycardia, a rise in heart rate from a basal heart rate of less than 10 beats/min/°C rise in temperature represents the lower border of the general febrile heart rate response of 10–18 beats/min/°C during infectious conditions [10, 11]. However, the application of alternative definitions of relative bradycardia would greatly affect our results. For example, a previous study defined relative bradycardia as an increase in pulse rate < 18 beats/min for each 1 °C increase in body temperature [5]. The prevalence of relative bradycardia in our population increased from 60.6 to 76.3% when this cut-off value was used. The definition of relative bradycardia was different in the previous two studies [4, 5]. The definition used in this study is the same definition of RB used in the diseases in which RB is accepted as a specific clinical feature (typhoid fever, scrubs typhus) [12]. Going forward, and for future studies, we suggest an unambiguous and unified definition be agreed upon.
The impact of COVID-19 infection on the cardiovascular system and its connection with bradycardia is likely multifactorial, and varies with disease severity as well as clinical setting. One of the most popular theories stems to the association of coronavirus and the angiotensin-converting enzyme 2 receptors [13]. It is likely that coronavirus has an inherent ability to invade the myocardial tissue. Although the mechanism of relative bradycardia is unclear, a hypothesis is that direct pathogen effects on the sinoatrial node and increased levels of inflammatory cytokines, such as interleukin-6, which was reported for patients with COVID-19, can increase vagal tone and decrease heart rate variability [14].
RB is a clinical term that is often used in daily practice and the literature as a clinical sign for an individual patient and a characteristic of some infectious diseases. The term has been defined in several studies [7] and can be an important diagnostic finding for variety of infectious diseases including Legionnaires’ disease, typhoid fever, psittacosis, typhus, leptospirosis, malaria, and babesiosis. RB may be used to differentiate among infectious diseases in specific clinical situations. Because the prevalence of RB in patients with COVID-19 was up to 60.6% in this study, it could also be used as a specific clinical feature to differentiate among similar infectious conditions.
In this study, basal heart rate was higher in the RB group than the GHRR group whereas the maximal heart rate was higher in the GHRR group. The RB group was older than GHRR group. These findings were consistent with previous studies, which presented that most cases occurred in patients over the age of 65 [15]. The RB did not seem to affect clinical outcomes in this study. This result may suggest that RB caused by COVID-19 does not mean critical cardiac manifestation.
Several limitations were present in this study. First, half of patients received antipyretic medicines during their hospitalization (acetaminophen was most commonly used). Because fever was possibly underestimated for these patients, relative bradycardia might be a more common clinical sign. Second, it was a study of patients admitted to tertiary hospitals, and many of them presented with severe conditions. Hence, the results may be different in more general patients. Moreover, relative bradycardia is a poorly defined clinical term, and further studies are needed to investigate its role in the diagnosis of COVID-19.
In conclusion, most patients with COVID-19 are associated with RB, not related to clinical outcome. RB in COVID-19 can be considered as the clinical features for differential diagnosis from other febrile conditions.