Case Report Theophylline in Treatment of COVID-19 Induced Sinus

Khalid Sawalha 1,* , Fuad J. Habash 2 , Srikanth Vallurupalli 2 and Hakan Paydak 3

1 Internal Medicine Division, White River Health System, Batesville, AR 72501, USA 2 Division, University of Arkansas for Medical Sciences, Little Rock, AR 72501, USA; [email protected] (F.J.H.); [email protected] (S.V.) 3 Electrophysiology Division, University of Arkansas for Medical Sciences, Little Rock, AR 72501, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-984-3641-158

Abstract: This is a retrospective case series of two patients with laboratory-confirmed coronavirus 2 (SARS-CoV-2) infection, presented to the University of Arkansas for Medical Sciences in January 2021. Medical records of these patients were reviewed using the EPIC electronic health record system. Clinical, laboratory, and treatment data were reviewed against periods of bradycardia in each patient. Both of the patients presented with and presyncope related to in which they received treatment with 1 mg of IV atropine and theophylline 200 mg orally. We share these two cases of theophylline treatment in COVID-19 induced sinus bradycardia. The first patient was a 39-year-old female, with a past medical history of polycystic ovarian syndrome, who presented to the emergency department with and dizziness. Two weeks prior to her presentation, she was tested positive for COVID-19 infection that was treated with azithromycin, dexamethasone and aspirin. Upon presentation, her ECG showed sinus bradycardia at a rate of 48 bpm. The second  patient, a 21-year-old female with no significant past medical history, presented with presyncope.  Three weeks prior to her presentation, she tested positive for COVID-19 infection that was treated Citation: Sawalha, K.; Habash, F.J.; symptomatically at her home. Upon presentation, her ECG showed at a rate Vallurupalli, S.; Paydak, H. of 51 bpm. Theophylline in Treatment of COVID-19 Induced Sinus Keywords: bradycardia; COVID-19; theophylline; bradyarrhythmias; junctional rhythm Bradycardia. Clin. Pract. 2021, 11, 332–336. https://doi.org/10.3390/ clinpract11020047 1. Introduction Received: 25 March 2021 Accepted: 26 May 2021 Sinus bradycardia is a rhythm in which the rate of impulses arising from the sinoatrial Published: 1 June 2021 (SA) node is lower than expected. The normal adult , arising from the SA node, is considered historically to range from 60 to 100 beats per minute, with sinus bradycardia

Publisher’s Note: MDPI stays neutral defined as a with a rate below 60 beats per minute. However, the normal with regard to jurisdictional claims in heart rate is, in part, the result of the complex interplay between the sympathetic and published maps and institutional affil- parasympathetic nervous systems. It is affected by numerous factors and varies in part iations. with age and physical conditioning [1,2]. Evaluation of beat-to-beat heart rate dynamics, as a result of autonomic nervous system function, is of main interest generally as a higher sympathetic activity unopposed by vagal activity promotes in a variety of ways, such as reducing ventricular refractory period and the ventricular fibrillation threshold, promoting triggered activity Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. afterpotentials and enhancing automaticity. Vagal stimulation opposes these changes and This article is an open access article reduces the effects of sympathetic stimulation by prolonging refractoriness, elevating the distributed under the terms and ventricular fibrillation threshold, and reducing automaticity. Furthermore, the fundamental conditions of the Creative Commons role of the autonomic nervous system in regulating inflammation, believed to underlie Attribution (CC BY) license (https:// many disease processes, is increasingly being appreciated. Increased sympathetic activity creativecommons.org/licenses/by/ promotes inflammation, and increased vagal activity moderates it [3,4]. 4.0/).

Clin. Pract. 2021, 11, 332–336. https://doi.org/10.3390/clinpract11020047 https://www.mdpi.com/journal/clinpract Clin. Pract. 2021, 12, FOR PEER REVIEW 2

The prevalence of and conduction system disease (and in general) in patients with COVID-19 varies from population to population. In most available reports, the specific cause of or types of arrhythmias have not been specified. and electrolyte abnormalities, both known to contribute to the development of acute arrhythmias, have been frequently reported in the acute phase of severe COVID-19 illness; therefore, the exact contribution of COVID-19 infection to the development of arrhythmias in asymptomatic, mildly ill, critically ill, and recovered pa- tients is unknown [3].

2. Case 1 Clin. Pract. 2021, 11 A 39-year-old female patient with a past medical history of polycystic ovarian syn-333 drome presented to the emergency department with lightheadedness and dizziness. Two weeks prior to her presentation, she was tested positive for COVID-19 infection after de- veloping symptoms of . She was quarantined at home and treated with The prevalence of arrhythmias and conduction system disease (and cardiovascular azithromycin, dexamethasone and aspirin. She denied smoking and alcohol or illicit drug disease in general) in patients with COVID-19 varies from population to population. In use. Upon her presentation, her physical examination was noted to be significant for brad- most available reports, the specific cause of palpitations or types of arrhythmias have ycardia.not been Her specified. vitals were Hypoxia blood and pressure electrolyte of 123/84 abnormalities, mmHg, heart both rate known of 35 beats to contribute per minute to ° (bpm),the development temperature of of acute 97.7 arrhythmias, F, and a respiratory have been rate frequently of 20 sating reported 100% in on the room acute air. phase Her electrocardiogramof severe COVID-19 showed illness; sinus therefore, bradycardia the exact without contribution any AV delay of COVID-19 or QRS prolongation infection to (Figurethe development 1A). This patient of arrhythmias wears a smart in asymptomatic, watch and she mildly showed ill, criticallyus her previous ill, and heart recovered rates werepatients in the is unknown ranges 70–90 [3]. s bpm before her COVID illness. Significant laboratory results included a WBC of 12.21 k/uL (3.60–9.50), troponin neg- ative2. Case at 1< 0.03 ng/mL (≤0.04), normal TSH at 2.65 uIU/mL (0.34–5.60), CRP at 5.9 mg/L (≤10.00),A 39-year-old ESR at 36 mm/h female (0–20), patient procalcitonin with a past at medical <0.02 ng/mL history (0.00–0.10), of polycystic a COVID-19 ovarian PCR syn- positive,drome presented BNP at to24 thepg/mL emergency (≤100), departmentand a negative with urine lightheadedness drug screen. and The dizziness. chest X-ray Two showedweeks prior no acute to her events. presentation, The transthoracic she was tested echocardiogram positive for was COVID-19 normal infectionwith an EF after of 55%.developing The patient symptoms was given of shortness 1 mg of of IV breath. atropine She with was quarantineda change of her at home rhythm and to treated sinus rhythmwith azithromycin, (Figure 1B). dexamethasoneGiven her response and to aspirin. atropine, She her denied presentation smoking was and likely alcohol related or illicit to herdrug SARS-CoV-2 use. Upon herinfection. presentation, She was her started physical on theophylline examination at was a 200 noted mg tooral be dose significant daily. Uponfor bradycardia. her follow up Her visit vitals one were week blood later, pressure she reported of 123/84 the improvement mmHg, heart of rateher ofsymptoms 35 beats withper minuteno side (bpm),effects temperaturefrom the theophylline. of 97.7 ◦F, La andter, aat respiratory her 6-week rate follow of 20up, sating the patient 100% re- on portedroom air. complete Her electrocardiogram resolution of her showed symptoms sinus and, bradycardia having resumed without anyher AVnormal delay daily or QRS ac- tivitiesprolongation and able (Figure to exercise1A). This normally patient wears with aher smart heart watch rate and ranging, she showed per her us smart her previous watch, betweenheart rates 100–130 were inbpm, the rangesthe decision 70–90 to s bpmdiscontinue before herthe COVIDtheophylline illness. was made.

(A) (B)

Figure 1. The ( A)) electrocardiogram electrocardiogram sinus sinus bradycardia bradycardia at at rate rate of of 48 48 beats beats per per minute, minute, and and ( (B)) scheme scheme 1 1 mg mg of of atropine atropine IV IV with normal sinus rhythm at rate 60 beats per minute.

3. CaseSignificant 2 laboratory results included a WBC of 12.21 k/µL (3.60–9.50), troponin negativeA 21-year-old at <0.03 ng/mL female (≤ patient0.04), normal with no TSH sign atificant 2.65 uIU/mL past medical (0.34–5.60), history CRP presented at 5.9 mg/L to the(≤10.00), emergency ESRat department 36 mm/h (0–20),with presyncope. procalcitonin Three at <0.02 weeks ng/mL prior (0.00–0.10),to her presentation, a COVID-19 she ≤ testedPCR positive, positive BNP for COVID-19 at 24 pg/mL infection ( 100), after and developing a negative urine symptoms drug screen. of shortness The chest of breath X-ray showed no acute events. The transthoracic echocardiogram was normal with an EF of 55%. The patient was given 1 mg of IV atropine with a change of her rhythm to sinus rhythm (Figure1B). Given her response to atropine, her presentation was likely related to her SARS-CoV-2 infection. She was started on theophylline at a 200 mg oral dose daily. Upon her follow up visit one week later, she reported the improvement of her symptoms with no side effects from the theophylline. Later, at her 6-week follow up, the patient reported complete resolution of her symptoms and, having resumed her normal daily activities and able to exercise normally with her heart rate ranging, per her smart watch, between 100–130 bpm, the decision to discontinue the theophylline was made.

3. Case 2 A 21-year-old female patient with no significant past medical history presented to the emergency department with presyncope. Three weeks prior to her presentation, she Clin. Pract. 2021, 11 334 Clin. Pract. 2021, 12, FOR PEER REVIEW 3

tested positive for COVID-19 infection after developing symptoms of shortness of breath andand chest . pain. She She was was quarantined quarantined at ather her home home and and treated treated symptomatically symptomatically with with im- provement.improvement. She She never never required required hospitalization hospitalization for for her her symptoms symptoms nor nor medications. medications. She denieddenied smoking smoking and alcohol alcohol or illicit illicit drug drug use use along along with with any any other other medication medication that could causecause QT QT interval prolongation. Upon Upon her her presentation, her physical examination was notednoted to be significantsignificant forfor bradycardia.bradycardia. HerHer vitals vitals were were blood blood pressure pressure of of 118/63 118/63 mmHg, mmHg, a aheart heart rate rate of of 45 45 bpm, bpm, a temperaturea temperature of of 98.3 98.3◦F, °F, and and a respiratorya respiratory rate rate of 18of sating18 sating 100% 100% on onroom room air. air. Her Her electrocardiogram electrocardiogram showed showed 45 bpm 45 bpm with with narrow narrow QRS QRS complex complex and and premature prem- atureatrial atrial complexes. complexes. SignificantSignificant laboratory results included a WB WBCC of 18.24 k/uL k/µL (3.60–9.50), (3.60–9.50), troponin troponin neg- neg- ativeative at <0.03 ng/mL ( (≤≤0.04),0.04), normal normal TSH TSH at at 3.79 3.79 uIU/mL (0.34–5.60), (0.34–5.60), CRP at 27.00 mg/Lmg/L ((≤≤10.00),10.00), ESR ESR at at 51 51 mm/h mm/h (0–20), (0–20), procalcitonin procalcitonin at <0.02 at <0.02 ng/mL ng/mL (0.00–0.10), (0.00–0.10), a COVID-19 a COVID-19 PCR positive,PCR positive, BNP BNPat 160 at pg/mL 160 pg/mL (≤100), (≤ lactate100), lactate at 1.2 atmmol/L 1.2 mmol/L (0.5–2.2), (0.5–2.2), and a andnegative a negative urine drugurine screen. drug screen. The chest The X-ray chest showed X-ray showed no acut noe events. acute events.The transthoracic The transthoracic echocardiogram echocar- wasdiogram normal was with normal an EF with of 60%. an EF The of patient 60%. The was patient walked was on walkedtreadmill on and treadmill her junctional and her heartjunctional rhythm heart increased rhythm to increased 91 bpm; toshe 91 was bpm; given she 1 was mg givenof atropine 1 mg ofIV atropineover a period IV over of 5 a min,period in ofwhich 5 min, her in sinus which rate her sinusincreased rate increasedto >100 bpm. to >100 Given bpm. the Given improvement the improvement in the pa- in tient’sthe patient’s symptoms, symptoms, there was there no wasindication no indication for a dual for chamber a dual chamber pacemaker. pacemaker. Hence, she Hence, was startedshe was on started theophylline on theophylline 200 mg oral 200 dose mg dail oraly dosewith dailyfollow with up within follow 1 upweek within at the 1 clinic week (Figureat the clinic 2A,B). (Figure Upon2 herA,B). follow Upon up, her she follow had a up, heart she rate had of a heart90 bpm rate while of 90 on bpm theophylline while on andtheophylline no side effects and nowere side reported. effects wereLater, reported. at her 5-week Later, follow at her up 5-week visit, a follow complete up resolu- visit, a tioncomplete of her resolution symptoms of was her symptomsreported and was theophylline reported and use theophylline was discontinued. use was discontinued.

(A) (B)

Figure 2. The ((AA)) electrocardiogramelectrocardiogram at at a a rate rate of of 45 45 beats beats per per minute, minute, and and (B )(B electrocardiogram) electrocardiogram with with junctional junctional rhythm rhythm and andresumption resumption of normal of normal sinus sinu rhythms rhythm after after theophylline. theophylline.

4.4. Discussion Discussion NormalNormal sinus sinus rhythm rhythm (NSR) is the characteri characteristicstic rhythm of the healthy heart. NSR is consideredconsidered to to be be present present in in adults adults if if the the he heartart rate rate is is between between 60 60 and and 100 100 beats beats per per minute, minute, thethe P-wave P-wave vector vector on on the the electrocardiogram electrocardiogram is is normal (consistent with SA nodal impulse origin),origin), and and the the rate rate is is mostly mostly regular. ArrhythmiasArrhythmias are are most commonly diagnosed from a combination of vital signs and a reviewreview of of the the EKG, EKG, ideally a 12-lead EKG, but a rhythm strip can also be used [[4].4]. SinusSinus bradycardia associatedassociated withwith infection infection might might include include viral viral or or bacterial bacterial etiologies, etiolo- gies,such such as: Lymeas: , disease, Chagas , disease, Legionella, Legionella, psittacosis, psittacosis, QQ fever,fever, typhoid fever, fever, typhus,typhus, babesiosis, babesiosis, malaria, malaria, leptospirosis, leptospirosis, yellow yellow fever, fever, dengue dengue fever, fever, viral hemorrhagic fevers,fevers, trichinosis, trichinosis, and and Rocky Rocky Mountain Mountain spotted spotted fever [5,6]. [5,6]. BradycardiaBradycardia has has been been reported reported with with COVID-19 COVID-19 infection infection since since the the pandemic’s pandemic’s start, start, butbut to to what what extent extent and and the the exact exact mechanisms mechanisms involved involved are still are stillunknown. unknown. One case One series case onseries four on patients four patients diagnosed diagnosed with COVID-19 with COVID-19 induced induced bradycardia bradycardia discussed discussed possible possible un- underlying mechanisms, such as: hypoxia, high levels of pro-inflammatory cytokines derlying mechanisms, such as: hypoxia, high levels of pro-inflammatory cytokines which which may directly affect the in which bradycardia develops, inflammatory may directly affect the sinoatrial node in which bradycardia develops, inflammatory and catecholamines status that may damage the cells, downregulation of

Clin. Pract. 2021, 11 335

and catecholamines status that may damage the cardiac pacemaker cells, downregulation of angiotensin-converting enzyme 2 (ACE2) receptor or even medications use [7]. Our patient presented with junctional rhythm in the setting of COVID-19 infection, manifested with an elevation of the ESR and CRP, which indicated that the inflammatory cytokines (mostly through IL-1) released during her immune response, acting on the cardiac pacemaker cells, could possibly have contributed to her presentation. According to the guidelines of American Heart Association (AHA) and Heart Rhythm Society (HRS), management of patients with asymptomatic bradycardia or pauses does not require placement of a permanent pacemaker [8]. Instead, these patients may be followed with intermittent examinations and observation. However, for patients with symptomatic bradycardia, implantation of a permanent pacemaker, rather than medical therapy or observation alone, is indicated according to the guidelines [8]. Symptoms of and lightheadedness are reversed in all patients following pacemaker placement, but there does not appear to be a survival benefit [9,10]. In a trial of 107 patients with symptomatic who were ran- domly assigned to no therapy, a rate-responsive pacemaker, or oral theophylline (which can increase heart rate by stimulation of the sympathetic nervous system or blockage of receptors as adenosine was shown to slow sinus rate and suppress the AV nodal conduction) [11] and followed for an average of 19 months, patients assigned to pacemaker therapy had a significantly lower incidence of syncope compared with those assigned to no therapy (6 versus 23 percent, respectively) and a trend towards less syncope when compared with those receiving theophylline (6 versus 17 percent, respectively) [12]. Implantation of a pacemaker and use of theophylline had an equivalent benefit on the inci- dence of compared with controls (3 versus 17 percent, respectively). Therefore, our patients were initiated on theophylline to stimulate their sympathetic system to restore normal sinus rhythm with a dose of 200 mg, taken orally daily, and a titrate as needed based on heart rate response and tolerability. According to the literature, daily doses of up to 900 mg/day have been reported [8]. Patients were educated and counseled about potential side effects of theophylline, including: nausea, vomiting, , tremors, headaches, insomnia, and restlessness. We followed our patients for one week after their discharge to monitor and assess their improvement as well as any potential side effects from the theophylline. No side effects were reported, and a significant improvement was noted. About one month after their initial follow up, another follow up showed the complete resolution of their symptoms and resumption of their daily life activities. Hence, theophylline use was discontinued. This decision was clinically made and driven by the resolution of symptoms as noted in this case series. If there was no significant improvement or persistency of their symptoms, further evaluation would be warranted such as Holter monitoring, stress testing, or even evaluation for pacemaker. There are limitations to our case series. First, our patients had oxygen saturation 100% on room air which indicates mild pulmonary infection. Other factors may have played a role in bradycardia other than SARS-COV-2, or the infection could have indirectly caused a disruption in the autonomic system balance, such as vagal hyperactivity, situa- tional reflexes, and pain response. Although the patients could have had asymptomatic bradycardia episodes, one of them had a smart watch that showed heart rate trends before hospitalization and she had never had such a low heart rate before the infection. Given that there was no other reversible cause of bradycardia, such as medications or any other obvious reason, we concluded that the symptomatic bradycardia was related to the infec- tion with SARS-COV-2, as it was the only significant change that occurred to both patients. Furthermore, resolution of the infection preceded the resolution of bradycardia-related symptoms and showed a positive heart rate trend during follow up in clinical encounters and vitals taken by the patients themselves at home. Clin. Pract. 2021, 11 336

5. Conclusions Our patients, described in this clinical vignette, had of bradycar- dia likely induced by their infection with the COVID-19 virus. Treatment with theophylline was proposed previously in the literature for symptomatic patients with sinus node dys- function, but studies have shown that a pacemaker is superior to theophylline. We used theophylline after the resolution of the patient’s symptoms with atropine to restore sinus rhythm as seen in these two cases.

Author Contributions: K.S.: writing and gathering information for the manuscript. F.J.H., S.V., and H.P.: reviewing the manuscript. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Our institution does not require ethical approval for report- ing individual cases or case series. Informed Consent Statement: Verbal consent was obtained directly from the patients. Data Availability Statement: Data available upon request. Conflicts of Interest: The authors declare no conflict of interest.

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