Clinical Features and Short-Term Outcomes in Virus-Induced Bradycardia: Comparison Between Covid and non-Covid Infected Patients

doi:10.21203/rs.3.rs-3112133/v1

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Clinical Features and Short-Term Outcomes in Virus-Induced Bradycardia: Comparison Between Covid and non-Covid Infected Patients

https://doi.org/10.21203/rs.3.rs-3112133/v1

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Covid-19 outbreak has drawn attention to the fact that viral infections might present with clinical bradycardia. Seeking its clinical significance, not yet unveiled by the literature, we come across other viral infections that also show clinical bradycardia during its clinical course, such as dengue fever and viral diarrhea. The clinical presentation of the latest seems to be severe, often presenting with orthostatic intolerance and fatigue symptoms, requiring expert consultation irrespective of the infection stage, and in case of dengue fever, frequently during the recovery phase. Meanwhile, in Covid-19 infected patients, the bradycardia observed is mild, frugal, and usually asymptomatic.

Thus, we conducted a comparison between two different groups of patients with viral infection displaying clinical bradycardia during hospital stay: Covid and non-Covid patients regarding clinical and Holter monitoring parameters. All patients had other causes of bradycardia excluded and echocardiography and cardiac biomarkers ruled out acute myocarditis.

The results showed that non-Covid patients presented with significantly lower mean and minimum heart rates (HR) on Holter monitoring, as well as longer times in with HR < 50 beats per minute (bpm). SDNN and pNN>50% were also significantly higher in non-Covid patients. The minimum systolic BP was significantly lower in non-Covid patients.

The study shows that Covid-19 is not the only viral infection that may display with clinical bradycardia, but it’s much milder than other viral infections such as dengue fever and viral diarrhea. It remains unclear the mechanism throughout Covid-related bradycardia comes about.

Cardiac & Cardiovascular Systems

sinus node dysfunction

autonomic nervous system

virus

infection

bradycardia

Acute changes in heart rate (HR) during infectious processes have been widely described.^1–4 Although the physiological response to infection is characterized by an elevation in HR due to an inflammatory process, some patients may paradoxically develop relative bradycardia,⁵ and actual clinically symptomatic bradycardia.^1–4

Several cases of transient bradycardia have been reported during the coronavirus disease 2019 (Covid-19) outbreak.^6,7 However, Covid is not the only viral infection that may present with clinical bradycardia. Different viral infections may also occur, with temporary clinical bradycardia.^1–4

These viral infections other than Covid-19 often reveal autonomic imbalance due to increased vagal tone, demonstrating low blood pressure (BP), orthostatic intolerance, and more severe bradycardia than that reported for Covid-19;^8,9 however, they have not yet been compared clinically.

This case series compared six non-Covid viral infection and eight Covid infection cases that presented with bradycardia during hospitalization at a single center in São Paulo, Brazil, regarding clinical features, bradycardia characteristics, and short-term outcomes.

Patients’ relevant clinical, laboratory, and electrocardiographic characteristics are shown in Tables 1 and 2 for Non-Covid and Covid patients, respectively.

Table 1. Non-Covid Patients

AGE, Acute Gastroenteritis; APh, Acute Pharyngitis; SR, sinus rhythm; F, female; LVEF, left ventricular ejection fraction; ECG, electrocardiogram; CT, computed tomography; MRI, magnetic resonance imaging; K, potassium; d-dimer normal range < 0.50; K normal range = 3.5–5.5 mEq/L. All patients showed normal levels of cardiac markers (Troponin < 0.16 ng/mL).

Table 2. Covid Patients

SAH, systemic arterial hypertension; DM, diabetes mellitus; DLP, dyslipidemia; AF, atrial fibrillation; SR, sinus rhythm; JR, junctional rhythm; F, female; M, male; LVEF, left ventricular ejection fraction; ECG, electrocardiogram; CT, computed tomography; MRI, magnetic resonance imaging; BNP, brain natriuretic peptide; TSH, thyroid stimulating hormone; K, potassium; FT4, free T4. All patients showed normal levels of cardiac markers (Troponin < 0.16 ng/mL). BNP reference value < 100 pg/mL; K normal range = 3.5–5.5 mEq/L; TSH normal range: 0.5–4.5 mUI/L; FT4 normal range: 0.8 − 1.8 ng/dL.

We retrospectively analyzed the data of patients admitted to a single center (Hospital Samaritano Higienopolis, United Health Group, São Paulo, Brazil) for viral infections that presented with bradycardia during the hospitalization between January 2017 and December 2021. The patients were divided into non-Covid and Covid groups. The Non-Covid group included an etiological diagnosis of dengue, acute gastroenteritis, and acute pharyngitis. Patients who used chronotropic-negative drugs were excluded from the trial. The hospital ethics committee approved this trial.

Both groups were compared regarding Holter monitoring data and minimum systolic BP and HR recorded during the hospital stay. Minimum HR could be recorded in the intensive care unit and the patient’s chart during the hospital stay, except for the Holter monitoring recording day. Parameters evaluated on Holter monitoring were mean HR, minimum HR, time (min) of HR < 50 bpm, standard deviation (SD) of normal-to-normal (NN) intervals (SDNN), and NN interval variation > 50% (PNN > 50%).

The 24 hr electrocardiogram-Holter utilized in all study patients was the Cardio Light recorder (Cardios, São Paulo, SP, Brazil), and the recording was analyzed using Cardio Smart 550 software. All the patients underwent Holter monitoring during their hospital stay.

We avoided evaluating relative bradycardia due to Faget’s sign since it could be misleading. Also, patients with previous heart disease were excluded from the trial. Moreover, patients presenting with acute myocarditis were also excluded from the trial.

Statistical Analysis

Data were presented as mean ± SD for numeric variables with normal distribution and median (interquartile range) for numeric variables with the non-parametric distribution. Comparisons of variables between non-Covid and Covid patients were made using Student’s t-test and Mann-Whitney test for normal numeric variables and non-parametric numeric variables, respectively. Multiple linear regressions were performed to understand the relationships between variables. Statistical significance was set at P ≤ 0.05.

Statistical analyses were performed using R Software Version 4 for Mac (R Foundation for Statistical Computing, Auckland, NZ).

The results of the comparison between the two groups are shown in Table 3. The results showed that non-Covid patients presented with significantly lower mean HR (49.16 bpm vs. 63.13 bpm, p = 0.021) and minimum HR (36.33 bpm vs. 46.12 bpm, p = 0.04) than Covid patients. Moreover, non-Covid patients presented with significantly greater time (min) of HR < 50 bpm than Covid patients. SDNN and pNN > 50% were also significantly higher in non-Covid patients. The minimum systolic BP was significantly lower in non-Covid patients. The minimum HR recorded during the hospital stay did not differ between groups.

Table 3

Comparison between Non-Covid vs. Covid Patients
	Non-COVID (n = 6)	COVID (n = 8)	p
Mean HR	49.16 ± 2.71	63.13 ± 12.48	0.021
Minimum HR	36.33 ± 1.86	46.12 ± 10.94	0.040
HR < 50 (min)	1035 (1011–1184)	38 (0–820)	0.043
SDNN	241 (192–265)	89 (70–188)	0.043
pNN > 50%	45.7 (34–53)	5.52 (3.4–15.5)	0.008
Lowest SBP	89.16 ± 8.81	109.00 ± 12.85	0.005
Lowest HR	44.66 ± 3.55	49.50 ± 6.61	0.107

An important aspect of this case series is that none of the patients presented with myocardial injury (troponin values were within normal range), inferring that there was no direct myocardial damage.

Our report compared two distinct groups of patients with viral infections presenting with clinical bradycardia: non-Covid and Covid. Although they shared common clinical symptoms and signs, we observed distinctive characteristics regarding the bradycardia features between these two groups on clinical evaluation.

Although bradycardia is not the most typical hemodynamic response to infectious processes, a minority of patients may present with this clinical feature.^1–4 This subject has recently been brought to light since the Covid-19 outbreak allowed the observation of clinical bradycardia among some infected patients.^6,7

However, we noticed that, although sharing bradycardia as a clinical feature, the severity of the HR alteration differs between the groups, and it is possible to recognize two distinct patterns: non-Covid patients typically demonstrated more severe lowering in HR, presenting with signs of more pronounced autonomic imbalance, such as low BP levels and orthostatic intolerance. Non-Covid patients were often symptomatic because of these marked disturbances. Notwithstanding, the vast majority of Covid patients presented with mild bradycardia without other clinical signs of autonomic imbalance and were usually asymptomatic.

Since non-Covid patients presented with marked signs of autonomic dysfunction, we analyzed and quantified hemodynamic and Holter monitoring parameters. All parameters, except minimum HR during the hospital stay were more exacerbated in this group than in the Covid group.

Before the Covid-19 pandemic, reports regarding virus-induced bradycardia were scarce in the literature. Sporadic reports of common viral infections, such as parainfluenza, described the development of bradycardia in the clinical specter.² Most reports describe dengue shock or the recovery phase of dengue infection presenting with severe bradycardia ^3,10,11. Additionally, Cellarier et al. described a patient who experienced inappropriate bradycardia during the Ebola virus disease.⁴

A report by Ha et al. also described the case of a 76-year-old patient with viral infection who presented with refractory cardiogenic shock due to severe sinus dysfunction, needing temporary pacing; however, this patient further presented with progressive limb weakness, developing Guillain-Barre Syndrome⁹. In this case, low BP and sinus bradycardia after viral infection were the first symptoms of acute autoimmune neuropathy. Most of the cases described corroborate our findings of more severe bradycardia and other signs of autonomic dysfunction, such as low BP levels and orthostatic intolerance.^{2–4, 8–11}

Regarding Covid-19-related bradycardia, initial reports showed that sinus bradycardia is a frequent finding in covid-19 patients; however, the degree of the bradycardia was not correlated with the severity of Covid-19 infection and the patient’s outcomes.^6,7,12

Nonetheless, results regarding the severity of bradycardia in Covid-19 are still conflicting. Some authors have described cases in which patients exhibited marked bradycardia or atrioventricular block, eliciting the need for a permanent pacemaker.^13,14 In contrast, others have shown that bradycardia has a relatively benign course and is often asymptomatic,^6,7 as the findings of this study support. Corroborating these findings, Akhtar et al. demonstrated that the prevalence of bradyarrhythmias requiring pacing during the Covid-19 pandemic did not increase.

Regarding the reason why non-Covid patients presented with marked bradycardia and signs of autonomic imbalance more often than Covid patients, we postulate that there is an impairment of beta-adrenergic receptors caused by autoimmune antibodies generated during non-Covid infection,⁸ while the bradycardia mechanism in Covid infection was related to direct viral action over the sinus node as well as cytokine storm (especially interleukin 6).⁶

This study has several limitations, including the small sample size, the retrospective design that may have introduced selection bias, and the fact that the study was conducted at a single center.

This report compared bradycardia features, an atypical finding in viral infections, between Covid and non-Covid patients. The latter demonstrated marked bradycardia and symptoms of autonomic dysfunction, possibly because of crossed reactions with autoimmune antibodies. Covid patients exhibited milder bradycardia and were often asymptomatic, indicating other possible mechanisms for rhythm disturbance. It is important to emphasize that the decrease in HR occurred independently of myocardial injury.

Thus, recognizing these features is important for the clinical identification of possible etiological agents and the clinical management of rhythm disorders. However, further studies with larger populations are needed to validate the findings of this case series and elucidate the bradycardia mechanism in each viral infection setting.

Table 3. The results show the mean value with standard deviation for each variable and the level of significance expressed by p-value. HR < 50 (min), SDNN, and pNN > 50% are expressed as median (interquartile range).

Conflict of interest statement: The authors disclosed no conflicts of interest.

Funding sources: This research did not receive grants from funding agencies in the public, commercial, or not-for-profit sectors.

Author Contributions: All authors contributed to the case report and literature review.

Marrie TJ. Mycoplasma pneumoniae pneumonia requiring hospitalization, with emphasis on infection in the elderly. Arch Intern Med. 1993 Feb 22;153(4):488-94.
Branche AR, Falsey AR. Parainfluenza Virus Infection. Semin Respir Crit Care Med. 2016 Aug;37(4):538-54. doi: 10.1055/s-0036-1584798. Epub 2016 Aug 3.
Carter R 3rd, Hinojosa-Laborde C, Convertino VA. Heart rate variability in patients being treated for dengue viral infection: new insights from mathematical correction of heart rate. Front Physiol. 2014 Feb 25; 5:46. doi: 10.3389/fphys.2014.00046
Cellarier G, Bordes J, De Greslan T, Karkowski L, Gagnon N, Billhot M, Cournac JM, Rousseau C, Mac Nab C, Dubrous P. Inappropriate bradycardia in Ebola virus disease. Med Sante Trop. 2016 Aug 1;26(3):283-286. English. doi: 10.1684/mst.2016.0586.
Ye F, Hatahet M, Youniss MA, Toklu HZ, Mazza JJ, Yale S. The Clinical Significance of Relative Bradycardia. WMJ. 2018 Jun;117(2):73-78.
Srinivasan A, Pansuriya T, Wilson B, Sarva ST, Jayaram T, Alim S, Kesavan R, Raza S. Systemic Inflammation-Related Bradycardia in COVID-19. Case Rep Cardiol. 2021 Sep 14; 2021:9986955. doi: 10.1155/2021/9986955.
Douedi S, Mararenko A, Alshami A, Al-Azzawi M, Ajam F, Patel S, Douedi H, Calderon D. COVID-19 induced bradyarrhythmia and relative bradycardia: An overview. J Arrhythm. 2021 Jun 14;37(4):888-892. doi: 10.1002/joa3.12578.
Fairchild KD, Srinivasan V, Moorman JR, Gaykema RP, Goehler LE. Pathogen-induced heart rate changes associated with cholinergic nervous system activation. Am J Physiol Regul Integr Comp Physiol. 2011 Feb;300(2): R330-9. doi: 10.1152/ajpregu.00487.2010.
Ha LD, Abbas F, Rao M. Gillian Barré Syndrome presenting with sinus node dysfunction and refractory shock. Am J Case Rep. 2017; 18:251-254.
Sharda M, Gupt A, Nagar D, Soni AK. Dengue fever: an additional cause for bradycardia. J Assoc Physicians India. 2014 Apr;62(4):362-3.
Kaushik JS, Gupta P, Rajpal S, Bhatt S. Spontaneous resolution of sinoatrial exit block and atrioventricular dissociation in a child with dengue fever. Singapore Med J. 2010 Sep;51(9): e146-8.
Stancampiano F, Omer M, Harris D, Valery J, Heckman M, White L, Libertin C. Clinical Characteristics and Outcomes of Patients Hospitalized for COVID-19 Pneumonia Who Developed Bradycardia. South Med J. 2021 Jul;114(7):432-437. doi: 10.14423/SMJ.0000000000001269.
Amir M, Yoseph H, Farisi ATA, Phie JKP, Adam ATS. Symptomatic Bradycardia in Covid-19 Hospitalized Patients: A Case Series. Int J Infect Dis. 2021 Oct; 111:1-4. doi: 10.1016/j.ijid.2021.07.068.
Ali M, Awadelkarim A, Bishop P, Alhusain R, Adam O, Subahi A, Elmoghrabi A, Afonso L. Severe Sinus Bradycardia: An Unusual Cardiac Manifestation of COVID-19. J Investig Med High Impact Case Rep. 2021 Jan-Dec; 9:23247096211013185. doi: 10.1177/23247096211013185.
Akhtar Z, Leung LW, Kontogiannis C, Zuberi Z, Bajpai A, Sharma S, Chen Z, Beeton I, Sohal M, Gallagher MM. Prevalence of bradyarrhythmias needing pacing in COVID-19. Pacing Clin Electrophysiol. 2021 Aug;44(8):1340-1346. doi: 10.1111/pace.14313.

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Clinical Features and Short-Term Outcomes in Virus-Induced Bradycardia: Comparison Between Covid and non-Covid Infected Patients

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Abstract

Introduction

Case Reports

Methods

Statistical Analysis

Results

Discussion

Conclusion

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References

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