Colchicine: A Possible COVID-19 Long haul Cardiac Therapy

Last Updated: December 16, 2021

Last Updated: December 16, 2021

Colchicine is an anti-inflammatory drug that is used to treat a variety of conditions, including gout, recurrent pericarditis, and familial Mediterranean fever.1 Recently, the drug has been shown to potentially reduce the risk of cardiovascular events in those with coronary artery disease.2 Colchicine has several potential mechanisms of action, including reducing the chemotaxis of neutrophils, inhibiting inflammasome signaling, and decreasing the production of cytokines, such as interleukin-1 beta.3 When colchicine is administered early in the course of COVID-19, these mechanisms could potentially mitigate or prevent inflammation-associated manifestations of the disease. These anti-inflammatory properties coupled with the drug’s limited immunosuppressive potential, favorable safety profile, and widespread availability have prompted investigation of colchicine for the treatment of COVID-19.

Recommendations

  • The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of colchicine for the treatment of nonhospitalized patients with COVID-19, except in a clinical trial (BIIa).
  • The Panel recommends against the use of colchicine for the treatment of hospitalized patients with COVID-19 (AI).

Rationale

For Nonhospitalized Patients With COVID-19

COLCORONA, a large randomized placebo-controlled trial that evaluated colchicine in outpatients with COVID-19, did not reach its primary efficacy endpoint of reducing hospitalizations and death.4 However, in the subset of patients whose diagnosis was confirmed by a positive SARS-CoV-2 polymerase chain reaction (PCR) result from a nasopharyngeal (NP) swab, a slight reduction in hospitalizations was observed among those who received colchicine.

PRINCIPLE, another randomized, open-label, adaptive-platform trial that evaluated colchicine versus usual care, was stopped for futility when no significant difference in time to first self-reported recovery from COVID-19 between the colchicine and usual care recipients was found.5

The PRINCIPLE trial showed no benefit of colchicine, and the larger COLCORONA trial failed to reach its primary endpoint, found only a very modest effect of colchicine in the subgroup of patients with positive SARS-CoV-2 PCR results, and reported more gastrointestinal adverse events in those receiving colchicine. Therefore, the Panel recommends against the use of colchicine for the treatment of COVID-19 in nonhospitalized patients, except in a clinical trial (BIIa).

For Hospitalized Patients With COVID-19

In the RECOVERY trial, a large randomized trial in hospitalized patients with COVID-19, colchicine demonstrated no benefit with regard to 28-day mortality or any secondary outcomes.6 Based on the results from this large trial, the Panel recommends against the use of colchicine for the treatment of COVID-19 in hospitalized patients (AI).

Clinical Data for COVID-19

Colchicine in Nonhospitalized Patients With COVID-19

The COLCORONA Trial

The COLCORONA trial was a contactless, double-blind, placebo-controlled, randomized trial in outpatients who received a diagnosis of COVID-19 within 24 hours of enrollment. Participants were aged ≥70 years or aged ≥40 years with at least 1 of the following risk factors for COVID-19 complications: body mass index ≥30, diabetes mellitus, uncontrolled hypertension, known respiratory disease, heart failure or coronary disease, fever ≥38.4°C within the last 48 hours, dyspnea at presentation, bicytopenia, pancytopenia, or the combination of high neutrophil count and low lymphocyte count. Participants were randomized 1:1 to receive colchicine 0.5 mg twice daily for 3 days and then once daily for 27 days or placebo. The primary endpoint was a composite of death or hospitalization by Day 30; secondary endpoints included components of the primary endpoint, as well as the need for mechanical ventilation by Day 30. Participants reported by telephone the occurrence of any study endpoints at 15 and 30 days after randomization; in some cases, clinical data were confirmed or obtained by medical chart reviews.4

Results

  • The study enrolled 4,488 participants.
  • The primary endpoint occurred in 104 of 2,235 participants (4.7%) in the colchicine arm and 131 of 2,253 participants (5.8%) in the placebo arm (OR 0.79; 95% CI, 0.61–1.03; P = 0.08).
  • There were no statistically significant differences in the secondary outcomes between the arms.
  • In a prespecified analysis of 4,159 participants who had a SARS-CoV-2 diagnosis confirmed by PCR testing of an NP specimen (93% of those enrolled), those in the colchicine arm were less likely to reach the primary endpoint (96 of 2,075 participants [4.6%]) than those in the placebo arm (126 of 2,084 participants [6.0%]; OR 0.75; 95% CI, 0.57–0.99; P = 0.04). In this subgroup of patients with PCR-confirmed SARS-CoV-2 infection, there were fewer hospitalizations (a secondary outcome) in the colchicine arm (4.5% of patients) than in the placebo arm (5.9% of patients; OR 0.75; 95% CI, 0.57–0.99).
  • More participants in the colchicine arm experienced gastrointestinal adverse events, including diarrhea which occurred in 13.7% of colchicine recipients versus 7.3% of placebo recipients (P < 0.0001). Unexpectedly, more pulmonary emboli were reported in the colchicine arm than in the placebo arm (11 events [0.5% of patients] vs. 2 events [0.1% of patients]; P= 0.01).

Limitations

  • Due to logistical difficulties with staffing, the trial was stopped at approximately 75% of the target enrollment, which may have limited the study’s power to detect differences for the primary outcome.
  • There was uncertainty as to the accuracy of COVID-19 diagnoses in presumptive cases.
  • Some patient-reported clinical outcomes were potentially misclassified.

The PRINCIPLE Trial

PRINCIPLE is a randomized, open-label, platform trial that evaluated colchicine in symptomatic, nonhospitalized patients with COVID-19 who were aged ≥65 years or aged ≥18 years with comorbidities or shortness of breath, and who had symptoms for ≤14 days. Participants were randomized to receive colchicine 0.5 mg daily for 14 days or usual care. The coprimary endpoints, which included time to first self-reported recovery or hospitalization or death due to COVID-19 by Day 28, were analyzed using a Bayesian model. Participants were followed through symptom diaries that they completed online daily; those who did not complete the diaries were contacted by telephone on Days 7, 14, and 29. The investigators developed a prespecified criterion for futility, specifying a clinically meaningful benefit in time to first self-reported recovery as a hazard ratio ≥1.2, corresponding to about 1.5 days of faster recovery in the colchicine arm.

Results

  • The study enrolled 4,997 participants: 212 participants were randomized to receive colchicine; 2,081 to receive usual care alone; and 2,704 to receive other treatments.
  • The prespecified primary analysis included participants with SARS-CoV-2 positive test results (156 in the colchicine arm; 1,145 in the usual care arm; and 1,454 in the other treatments arm).
  • The trial was stopped early because the criterion for futility was met; the median time to self-reported recovery was similar in the colchicine arm and the usual care arm (HR 0.92; 95% CrI, 0.72–1.16).
  • Analyses of self-reported time to recovery and hospitalizations or death due to COVID-19 among concurrent controls also showed no significant differences between the colchicine and usual care arms.
  • There were no statistically significant differences in the secondary outcomes between the colchicine and usual care arms in both the primary analysis population and in subgroups, including subgroups based on symptom duration, baseline disease severity, age, or comorbidities.
  • The occurrence of adverse events was similar in the colchicine and usual care arms.

Limitations

  • The design of the study was open-label treatment.
  • The sample size of the colchicine arm was small.

Colchicine in Hospitalized Patients With COVID-19

The RECOVERY Trial

In the RECOVERY trial, hospitalized patients with COVID-19 were randomized to receive colchicine (1 mg loading dose, followed by 0.5 mg 12 hours later, and then 0.5 mg twice daily for 10 days or until discharge) or usual care.6

Results

  • The study enrolled 11,340 participants.
  • At randomization, 10,603 patients (94%) were receiving corticosteroids.
  • The primary endpoint of all-cause mortality at Day 28 occurred in 1,173 of 5,610 participants (21%) in the colchicine arm and 1,190 of 5,730 participants (21%) in the placebo arm (rate ratio 1.01; 95% CI, 0.93–1.10; P = 0.77).
  • There were no statistically significant differences between the arms for the secondary outcomes of median time to being discharged alive, discharge from the hospital within 28 days, and receipt of mechanical ventilation or death.
  • The incidence of new cardiac arrhythmias, bleeding events, and thrombotic events was similar in the 2 arms. Two serious adverse events were attributed to colchicine: 1 case of severe acute kidney injury and one case of rhabdomyolysis.

Limitations

  • The trial’s open-label design may have introduced bias for assessing some of the secondary endpoints.

The GRECCO-19 Trial

GRECCO-19 was a small, prospective, open-label randomized clinical trial in 105 patients hospitalized with COVID-19 across 16 hospitals in Greece. Patients were assigned 1:1 to receive standard of care with colchicine (1.5 mg loading dose, followed by 0.5 mg after 60 minutes and then 0.5 mg twice daily until hospital discharge or for up to 3 weeks) or standard of care alone.7

Results

  • Fewer patients in the colchicine arm (1 of 55 patients) than in the standard of care arm (7 of 50 patients) reached the primary clinical endpoint of deterioration in clinical status from baseline by 2 points on a 7-point clinical status scale (OR 0.11; 95% CI, 0.01–0.96).
  • Participants in the colchicine group were significantly more likely to experience diarrhea (occurred in 45.5% of participants in the colchicine arm vs. 18.0% in the standard of care arm; P = 0.003).

Limitations

  • The overall sample size and the number of clinical events reported were small.
  • The study design was open-label treatment assignment.

The results of several small randomized trials and retrospective cohort studies that have evaluated various doses and durations of colchicine in hospitalized patients with COVID-19 have been published in peer-reviewed journals or made available as preliminary, non-peer-reviewed reports.8-11 Some have shown benefits of colchicine use, including less need for supplemental oxygen, improvements in clinical status on an ordinal clinical scale, and reductions in certain inflammatory markers. In addition, some studies have reported higher discharge rates or fewer deaths among patients who received colchicine than among those who received comparator drugs or placebo. However, the findings of these studies are difficult to interpret due to significant design or methodological limitations, including small sample sizes, open-label designs, and differences in the clinical and demographic characteristics of participants and permitted use of various cotreatments (e.g., remdesivir, corticosteroids) in the treatment arms.

Adverse Effects, Monitoring, and Drug-Drug Interactions

Common adverse effects of colchicine include diarrhea, nausea, vomiting, abdominal cramping and pain, bloating, and loss of appetite. In rare cases, colchicine is associated with serious adverse events, such as neuromyotoxicity and blood dyscrasias. Use of colchicine should be avoided in patients with severe renal insufficiency, and patients with moderate renal insufficiency who receive the drug should be monitored for adverse effects. Caution should be used when colchicine is coadministered with drugs that inhibit cytochrome P450 (CYP) 3A4 and/or P-glycoprotein (P-gp) because such use may increase the risk of colchicine-induced adverse effects due to significant increases in colchicine plasma levels. The risk of myopathy may be increased with the concomitant use of certain HMG-CoA reductase inhibitors (e.g., atorvastatin, lovastatin, simvastatin) due to potential competitive interactions mediated by CYP3A4 and P-gp pathways.12,13 Fatal colchicine toxicity has been reported in individuals with renal or hepatic impairment who received colchicine in conjunction with P-gp inhibitors or strong CYP3A4 inhibitors.

Considerations in Pregnancy

There are limited data on the use of colchicine in pregnancy. Fetal risk cannot be ruled out based on data from animal studies and the drug’s mechanism of action. Colchicine crosses the placenta and has antimitotic properties, which raises a theoretical concern for teratogenicity. However, a recent meta-analysis did not find that colchicine exposure during pregnancy increased the rates of miscarriage or major fetal malformations. There are no data for colchicine use in pregnant women with acute COVID-19. Risks of use should be balanced against potential benefits.12,14

Considerations in Children

Colchicine is most commonly used in children to treat periodic fever syndromes and autoinflammatory conditions. Although colchicine is generally considered safe and well tolerated in children, there are no data on the use of the drug to treat pediatric acute COVID-19 or multisystem inflammatory syndrome in children (MIS-C).

References

  1. van Echteld I, Wechalekar MD, Schlesinger N, Buchbinder R, Aletaha D. Colchicine for acute gout. Cochrane Database Syst Rev. 2014(8):CD006190. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25123076.
  2. Xia M, Yang X, Qian C. Meta-analysis evaluating the utility of colchicine in secondary prevention of coronary artery disease. Am J Cardiol. 2021;140:33-38. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33137319.
  3. Reyes AZ, Hu KA, Teperman J, et al. Anti-inflammatory therapy for COVID-19 infection: the case for colchicine. Ann Rheum Dis. 2021 May;80(5):550-557. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33293273.
  4. Tardif JC, Bouabdallaoui N, L’Allier PL, et al. Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial. Lancet Respir Med. 2021;9(8):924-932. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34051877.
  5. PRINCIPLE Trial Collaborative Group, Dorward J, Yu L, et al. Colchicine for COVID-19 in adults in the community (PRINCIPLE): a randomised, controlled, adaptive platform trial. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.09.20.21263828v1.
  6. RECOVERY Collaborative Group. Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet Respir Med. 2021;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34672950.
  7. Deftereos SG, Giannopoulos G, Vrachatis DA, et al. Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the GRECCO-19 randomized clinical trial. JAMA Netw Open. 2020;3(6):e2013136. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32579195.
  8. Brunetti L, Diawara O, Tsai A, et al. Colchicine to weather the cytokine storm in hospitalized patients with COVID-19. J Clin Med. 2020;9(9). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32937800.
  9. Sandhu T, Tieng A, Chilimuri S, Franchin G. A case control study to evaluate the impact of colchicine on patients admitted to the hospital with moderate to severe COVID-19 infection. Can J Infect Dis Med Microbiol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33133323.
  10. Lopes MI, Bonjorno LP, Giannini MC, et al. Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial. RMD Open. 2021;7(1). Available at: https://www.ncbi.nlm.nih.gov/pubmed/33542047.
  11. Salehzadeh F, Pourfarzi F, Ataei S. The impact of colchicine on the COVID-19 patients; a clinical trial. Research Square. 2020;Preprint. Available at: https://www.researchsquare.com/article/rs-69374/v1.
  12. Colchicine (Colcrys) [package insert]. Food and Drug Administration. 2012. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf.
  13. American College of Cardiology. AHA statement on drug-drug interactions with statins. 2016. Available at: https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2016/10/20/21/53/recommendations-for-management-of-clinically-significant-drug. Accessed November 2, 2021.
  14. Indraratna PL, Virk S, Gurram D, Day RO. Use of colchicine in pregnancy: a systematic review and meta-analysis. Rheumatology (Oxford). 2018;57(2):382-387. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29029311.

www.covid19treatmentguidelines.nih.govAn official website of the National Institutes of Health

Electrocardiographic Changes in COVID-19 Patients: A Hospital-based Descriptive Study

Authors: Deepalakshmi Kaliyaperumal,1Kumar Bhargavi,2Karthikeyan Ramaraju,3Krishna S Nair,4Sudha Ramalingam,5 and Murali Alagesan6

Indian J Crit Care Med. 2022 Jan; 26(1): 43–48.doi: 10.5005/jp-journals-10071-24045PMCID:  PMC8783240PMID: 35110843

Abstract

Background

Coronavirus disease-2019 (COVID-19) infection is a multisystem disease not restricted to the lungs. It has a negative impact on the cardiovascular system by causing myocardial damage, vascular inflammation, plaque instability, and myocardial infarction. The presence of myocardial injury is a poor prognostic sign. Electrocardiogram (ECG), a simple bedside diagnostic test with high prognostic value, can be employed to assess early cardiovascular involvement in such patients. Various abnormalities in ECG like ST-T changes, arrhythmia, and conduction defects have been reported in COVID-19. We aimed to find out the ECG abnormalities of COVID-19 patients.

Methods

We performed a cross-sectional, hospital-based descriptive study among 315 COVID-19 in-patients who underwent ECG recording on admission. Patients’ clinical profiles were noted from their records, and the ECG abnormalities were studied.

Results

Among the abnormal ECGs 255 (81%), rhythm abnormalities were seen in 9 patients (2.9%), rate abnormalities in 115 patients (36.5%), and prolonged PR interval in 2.9%. Short QRS complex was seen in 8.3%. QT interval was prolonged in 8.3% of the patients. Significant changes in the ST and T segments (42.9%) were observed. In logistic regression analysis, ischemic changes in ECG were associated with systemic hypertension and respiratory failure.

Conclusion

In our study, COVID-19 patients had ischemic changes, rate, rhythm abnormalities, and conduction defects in their ECG. With this ongoing pandemic of COVID-19 and limited health resources, ECG—a simple bedside noninvasive tool is highly beneficial and helps in the early diagnosis and management of cardiac injury.

How to cite this article

Kaliyaperumal D, Bhargavi K, Ramaraju K, Nair KS, Ramalingam S, Alagesan M. Electrocardiographic Changes in COVID-19 Patients: A Hospital-based Descriptive Study. Indian J Crit Care Med 2022;26(1):43–48.Keywords: Coronavirus disease-2019, Electrocardiogram change, Rate abnormalities, ST-T changes

Introduction

A cluster of pneumonia cases were reported due to “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2) at the end of 2019 in the city of Wuhan, in the Hubei Province of China. Soon coronavirus disease-2019 (COVID-19) was declared as a pandemic owing to its rapid spread across the countries.1 Initially regarded as a respiratory infection, COVID-19 is now known to affect all major systems in the body. Quite a lot is discussed in literature last year about COVID-19 and its effect on lungs and systemic response. However, very little is debated about cardiovascular involvement in COVID. It has been observed that lung involvement is more severe in patients with preexisting cardiac involvement. However, in sharp contrast new-onset cardiac involvement is also noted in a few patients and few patients do present with cardiac symptoms alone without lung involvement.2 The spectrum of presentation is wide-ranging from patients having no cardiac disease at all, asymptomatic but with elevated cardiac markers, having symptoms of overt cardiac disease such as angina, cardiogenic shock, heart failure, cardiac arrhythmias, and sudden cardiac death.

Arrhythmia and acute cardiac injury were reported in 16.7 and 7.2% of the COVID patients.3 In addition to the systemic inflammatory response, the physiological mechanisms identified to cause cardiac involvement in COVID-19 patients are hypoxemia-related myocardial cell injury and endothelial cell damage due to upregulated expression of angiotensin-converting enzyme 2 (ACE 2) in the heart and lungs.4

The electrocardiogram (ECG) changes reflect cardiac involvement with diverse manifestations. Arrhythmia and conduction defects are found to be more prevalent among SARS-CoV-2-infected individuals.5 Myocardial ischemia, myocarditis, shock, hypoxia, and electrolyte abnormalities were the factors identified to cause arrhythmias.6 The presence of cardiac involvement may imply poor prognosis and an adverse outcome.7 Therefore, it is pertinent to assess and monitor the cardiac abnormalities paving way for a prompt action. ECG, a simple bedside diagnostic test with high prognostic value, can be employed to assess cardiovascular involvement in COVID-19 patients. We aimed to find out the ECG abnormalities of patients with SARS-CoV-2 infection.

Materials and Methods

This cross-sectional, hospital-based descriptive study was conducted among 315 COVID-19 patients admitted in our tertiary care center during October to December 2020 after obtaining the human institutional ethics committee clearance and informed consent from the patients participating in the study [IHEC NO: Project No: 20/217]. Patients whose COVID status was confirmed by real-time reverse transcriptase polymerase chain reaction on nasopharyngeal and oropharyngeal swabs were included in the study.

Consecutive patients admitted to our hospital with SARS-CoV-2-positive status underwent ECG testing on admission and were included in the study. Patients’ clinical profiles that include symptoms, duration, and severity of illness, and comorbid status were noted from their clinical records. ECGs were reviewed and interpreted by two physicians (together responsible for the interpretation of >100,000 ECGs per year) who were blinded to the clinical status of the patients. Patients with ventricular pacing, immune suppression, stroke, malignancy and patients on beta blockers and anti-arrhythmic drugs were excluded.

The ECG data include heart rate, rhythm categorized as normal sinus rhythm or atrial fibrillation/flutter, atrial premature contractions, ventricular premature contractions, atrioventricular block, axis deviation, bundle branch block, intraventricular conduction block (QRS duration of >110 ms), Bazett-corrected QT interval (in milliseconds), presence of left or right ventricular hypertrophy, myocardial infarction, and the presence of ST segment or T-wave changes (localized ST elevation, localized T-wave inversion, or other nonspecific repolarization abnormalities).

Statistical Analysis

The data collected from the patients were tabulated using Microsoft Excel. Descriptive statistics were employed for analysis. Data were expressed as mean ± standard deviation for continuous variables and proportions for categorical variables. Logistic regression analysis was employed to study the association between clinical variables and occurrence of various types of ECG abnormalities. The results were expressed in odds ratio with 95% confidence interval after adjusting for important confounders.

Results

A total of 315 patients satisfying the inclusion criteria were included in the study. Out of the total 315 patients studied, 92 (29.2%) were females and 223 (70.8%) were males with an average age of 52.6 ± 16.3 years. Clinical characteristics like symptoms on admission, severity and duration of illness, duration of the hospital stay, disease course, and outcomes are depicted in Table 1.

Table 1

Demographic and clinical characteristics of the study population

Demographic and clinical variablesN = 315
Age (mean±SD)52.6±16.3
Age distribution 
15–30years29 (9.2%)
31–45years77 (24.4%)
46–60years100 (31.7%)
61–75years83 (26.3%)
>75years26 (8.2%)
Gender 
Male223 (70.8%)
Female92 (29.2%)
Duration of illness (at admission) 
Median duration (days)3
Range (days)0–30
Symptomatology 
Asymptomatic69 (21.9%)
Symptomatic (at least one of the below)246 (78.1%)
Fever154 (62.6%)
Cough133 (54.0%)
Breathlessness74 (30.0%)
Diarrhea32 (13.0%)
Anosmia/ageusia21 (8.5%)
Others98 (39.8%)
Comorbidities 
Diabetes mellitus116 (36.8%)
Systemic hypertension96 (30.5%)
Heart diseases30 (9.5%)
Respiratory diseases15 (4.6%)
Thyroid diseases13 (4.1%)
Kidney diseases4 (1.3%)
At least one comorbid illness139 (44.1%)
No comorbidities176 (55.9%)
Disease course during hospital stay 
Clinical deterioration68 (21.6%)
Clinically stable and improving231 (73.3%)
Subjects with oxygen requirement108 (34.3%)
Subjects with ICU admission (>48hours)63 (20.0%)
Duration of hospital stay 
Median duration (days)9.00
Range (days)1–32
Outcomes 
Discharged296 (93.9%)
Died (in-hospital mortality—all-cause mortality)19 (6.0%)

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ECG abnormalities encountered in the study population with respect to the rate, rhythm, PR interval, axis deviation, QRS complex, QT interval, and ST and T-wave changes are shown in Figure 1.

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ECG abnormalities in the study population

Among the abnormal ECGs 255 (81%), rhythm abnormalities were seen in 9 patients (2.9%); rate abnormalities in 115 patients (36.5%)—bradycardia (12.7%) and tachycardia (23.8%); and prolonged PR interval in 2.9% patients. Short QRS complex was seen in 8.3%. QT interval was prolonged in 8.3% of the patients. There were significant changes in the ST and T segments (Table 2).

Table 2

Distribution of ECG changes at admission among the study population

ECG changesFrequency (%) (N = 315)
Normal ECG60 (19.0%)
Irregular rhythm9 (2.9%)
Abnormal rate
Sinus bradycardia40 (12.7%)
Sinus tachycardia95 (23.8%)
Axis deviation
Left91 (28.9%)
Right0 (0.0%)
PR interval
Shortened PR interval4 (1.4%)
Prolonged PR interval9 (2.9%)
QRS complex
Short QRS complex26 (8.3%)
Widened QRS complex9 (2.9%)
Poor progression of R-waves91 (28.9%)
QT interval
Shortened QT interval25 (7.9%)
Prolonged QT interval26 (8.3%)
ST segment
ST elevation27 (8.6%)
ST depression16 (5.1%)
ST flattening/coving10 (3.2%)
T-waves
T-wave inversion75 (23.8%)
Tall T-waves7 (2.2%)

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In logistic regression model (Table 3), subjects with moderate-to-severe COVID-19 illness were twice likely to have at least one of the above-described abnormalities in ECG independent upon age, gender, and preexisting cardiac diseases [adjusted odds ratio 2.02 (95% confidence interval 1.04–3.95)]. Among all subjects, ischemic changes in ECG (ST segment changes and T-wave inversion) appeared to be associated with systemic hypertension [adjusted odds ratio 1.73 (95% confidence interval 0.96–3.11)] and respiratory failure [adjusted odds ratio 1.58 (95% confidence interval 0.94–2.66)] after adjusting age, gender, and preexisting heart diseases. The above-mentioned associations showed a trend toward statistical significance. No other ECG changes had any significant association with clinical variables studied.

Table 3

Logistic regression analysis of association between ECG changes and clinical variables

Variable-associated ECG abnormalitiesUnadjusted odds ratio (95% confidence interval)Adjusted odds ratio (95% confidence interval)
Ischemic changes in ECG (ST segment elevation/depression and/or T inversion)
Systemic hypertension1.84 (1.113–3.055)*1.73 (0.96–3.11)
Respiratory failure on admission1.71 (1.049–2.79)*1.58 (0.94–2.66)

Open in a separate windowAdjustment model: age, gender, and preexisting heart diseases.*p <0.05

Of the 315 patients, 19 patients died ultimately due to COVID. The ECG abnormalities studied in these patients are shown in Figure 2. Prolongation of QTc interval (42%) and tachycardia (36.8%) were the commonest changes noted in them. The various ECG abnormalities encountered in the study population and the outcomes in each group are depicted in Figure 3. Adverse final outcomes were noted in 11.5% of the patients who had ST-T changes and QTc prolongation and 8.4% of the patients who had tachycardia.

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Pie chart showing the final outcomes of the study population and various ECG abnormalities in the deceased population

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Stacked column chart depicting the various ECG abnormalities and patient outcomes in each category

Discussion

Myocardial injury associated with cardiac dysfunction and arrhythmias has been reported in infectious diseases. ECG changes observed in infections include hemorrhagic fever,8,9 leptospirosis,10 scrubtyphus,11 diphtheria,12 trichinellosis,13 and trypanosomiasis.14 Myocardial injury observed in dengue viral infection is evidenced by the presence of ECG abnormalities like atrial and ventricular premature beats, prolonged PR interval, bundle branch block s, and ST and T segment changes.15 Abnormal ECG findings were found to be reported in 28% of the hospitalized patients infected with novel H1N1 influenza virus.16 Similarly, now there is growing evidence that SARS-CoV-2 also has the potential to have a negative impact on the cardiovascular system.

There are multiple proposed mechanisms for cardiac damage in COVID-19. These include cytokine release syndrome,17 direct myocardial damage as in viral myocarditis due to the interaction between virus and ACE 2,18,19 coronary spasm, induction of a hypercoagulable state, plaque instability causing rupture, and acute coronary syndrome.20 Other potential mechanisms may include cardiac toxicity due to antivirals, steroids, and electrolyte abnormalities.

Even the earliest cases in China had evidence of myocardial injury21 and previous studies did estimate the prevalence as between 1 and 7% of the patients and 26% required intensive care.22 Studies by Shi et al. also inferred that cardiac involvement was associated with high mortality.23

In our study, we observed sinus tachycardia (23.8%), sinus bradycardia (12.7%), and atrial arrhythmia (3.5%). This is in accordance with a study by Brit Long where the commonest ECG abnormality in COVID patients was sinus tachycardia followed by atrial fibrillation, ventricular arrhythmias, QTc prolongation, and ST-T segment changes.24 Atrial fibrillation (3.5%), bradyarrhythmia (1.2%), and nonsustained VT (10.4%) were reported in another study conducted among 700 patients with severe acute respiratory syndrome due to SARS-CoV-2 infection.25

In our study, we encountered ischemic changes (ST segment elevation, T-wave inversion) in 32.4% of the COVID-19 patients irrespective of their underlying cardiac health. Italy published a research study of 28 COVID-19 patients who underwent angiogram for ST elevation myocardial infarction in whom 86% had STEMI as the first presentation of COVID showing that acute coronary event had preceded systemic inflammation. Of these, 79% had typical chest pain, while 21% presented with dyspnea without any chest pain.26

In the present study, 16.2% of the COVID-19 patients presented with QT segment changes (prolonged and shortened). QT interval prolongation has been noted in about 13% of the COVID-19 patients. Major contributing factors to this particular abnormality may be the list of several (now unapproved) drugs previously used for COVID-19 treatment like hydroxychloroquine and azithromycin.27,28 QT interval prolongation may cause rhythm disturbances and hemodynamic instability requiring ICU admission and if not attended to may cause sudden cardiac death.

Pulmonary embolism may be a presenting issue of COVID-19 as well as its complication. A recent study of ECG findings in pulmonary embolism in COVID patients showed that abnormalities were mostly nonspecific including sinus tachycardia and minimal ST segment or T-wave changes. Specific and classic findings (classic S1Q3T3 pattern) were seen in less than 10% of the patients.29

All the 19 COVID patients who had succumbed to death had abnormal ECG findings. In a retrospective study to highlight the prognostic significance of ECG in COVID, Yang et al. have compared the ECG changes in survivors and nonsurvivors.30 It was observed that the nonsurvivors had significantly higher rates of prolonged QTc interval, axis deviation, arrhythmias, ST-T changes, and an overall higher abnormal ECG score. In our study population, QTc prolongation and tachycardia were the commonest changes in the deceased.

In a retrospective ECG analysis in the COVID-19 patients, Wang et al. have studied the ECG characteristics in the critically severe and severe group of patients.31 He has observed that 84.5% of the patients had abnormal ECG findings in the critically severe group as against 53% in the severe group. ST-T changes (48.5%) and sinus tachycardia (30%) were the most common abnormalities noted in the critically severe group of patients. In our study population, mortality was observed in 11.5% of the patients who had ST-T changes, 11.5% of the patients who had QTc prolongation, and 8.4% of those who had sinus tachycardia.

Limitations

Other factors that influence the ECG findings such as age, body mass index (BMI), electrolyte imbalances, inflammatory markers, and specifically cardiac markers were not considered in the analysis. We wish to extend the present study to find out the influence of SARS-CoV-2 virus on electrophysiology of cardiac muscle excluding these factors that affect the ECG parameters. Moreover, correlation of ECG findings with echocardiogram, clinical outcomes, and follow-up will help us understand the pathophysiology of cardiac diseases in COVID-19 disease. This will strengthen the race against COVID infection by enriching our knowledge and unraveling further mysteries around this mysterious infection.

Conclusion

In our study, COVID-19 patients presented with ischemic changes, rhythm abnormalities, and conduction defects. With SARS-CoV-2 having already gained momentum worldwide, it is important to deploy simple, cost-effective bedside examination, and diagnostic tests considering our limited health resources. ECG is of paramount importance in the Emergency COVID Department too as it is central to risk stratification and is predictive of an adverse outcome.

Highlights

  • SARS-CoV-2 extends its prongs well beyond the lungs.
  • There are multiple mechanisms for myocardial damage in COVID-19.
  • Myocardial injury when present is a poor prognostic sign.
  • ECG is a simple bedside diagnostic test to screen for cardiac abnormalities.
  • The commonest ECG abnormalities in our study were sinus tachycardia, ischemic changes, and QTc segment abnormalities.
  • It is crucial to monitor the patients for cardiac manifestations that will help to identify the complications and initiate prompt treatment.

Orcid

Deepalakshmi Kaliyaperumal https://orcid.org/0000-0002-3589-3860

Kumar Bhargavi https://orcid.org/0000-0002-9799-0332

Karthikeyan Ramaraju https://orcid.org/0000-0002-5577-5829

Krishna S Nair https://orcid.org/0000-0002-5339-6470

Sudha Ramalingam https://orcid.org/0000-0001-7800-9396

Murali Alagesan https://orcid.org/0000-0002-5876-4033Go to:

Footnotes

Source of support: Nil

Conflict of interest: NoneGo to:

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Articles from Indian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine are provided here courtesy of Indian Society of Critical Care Medicine

Five months post-covid, Nicole Murphy’s heart rate is still doing strange things

Authors: Ariana Eunjung Cha February 21, 2022

The Washington Post
The Washington Post

Five months after being infected with the coronavirus, Nicole Murphy’s pulse rate is going berserk. Normally in the 70s, which is ideal, it has been jumping to 160, 170 and sometimes 210 beats per minute even when she is at rest — putting her at risk of a heart attack, heart failure or stroke.

No one seems to be able to pinpoint why. She’s only 44, never had heart issues, and when a cardiologist near her hometown of Wellsville, Ohio, ran all of the standard tests, “he literally threw up his hands when he saw the results,” she recalled. Her blood pressure was perfect, there were no signs of clogged arteries, and her heart was expanding and contracting well.

Murphy’s boomeranging heart rate is one of a number of mysterious conditions afflicting Americans weeks or months after coronavirus infections that suggest the potential of a looming cardiac crisis.

A pivotal study that looked at health records of more than 153,000 U.S. veterans published this month in Nature Medicine found that their risk of cardiovascular disease of all types increased substantially in the year following infection, even when they had mild cases. The population studied was mostly White and male, but the patterns held even when the researchers analyzed women and people of color separately. When experts factor in the heart damage probably suffered by people who put off medical care, more sedentary lifestyles and eating changes, not to mention the stress of the pandemic, they estimate there may be millions of new onset cardiac cases related to the virus, plus a worsening of disease for many already affected.

“We are expecting a tidal wave of cardiovascular events in the coming years from direct and indirect causes of covid,” said Donald M. Lloyd-Jones, president of the American Heart Association.

In February 2021, the National Institutes of Health launched an initiative to look at the causes and possible treatments for long covid, the constellation of symptoms from brain fog and exercise fatigue to heart-related issues that some people experience well past their initial infections. In addition, the American College of Cardiology has recognized the serious, longer-term effects of the coronavirus by preparing new guidelines, scheduled out in March, for monitoring and returning to exercise after infection. But many experts and patient advocacy groups say more is needed, and are calling on President Biden and other leaders for comprehensive changes in the health care system that would provide more funding for research and treatment, financial support for people who can no longer work and address the social and emotional consequences of illness in the decades to come.

Zaza Soriano, 32, a software engineer from Millersville, Md., who works for a NASA subcontractor, got covid right before Christmas despite being fully vaccinated and boosted, and since then, her blood pressure has remained very high with the bottom number, or diastolic pressure when the heart rests between beats sometimes as high as 110 when it should be lower than 80. She also has brain fog and her joints ache.

“It’s so frustrating we still know so little about why this is happening,” she said.

Ziyad Al-Aly, an assistant professor of medicine at Washington University and a Veterans Affairs physician who co-authored the Nature Medicine study, describes the pandemic as an earthquake. “When the earth stops shaking and the dust settles, we will have to be able to deal with the aftermath on heart and other organ systems,” he said.

“Governments around the world need to pay attention,” Al-Aly emphasized. “We are not sufficiently prepared.”

Heart disease is the planet’s No. 1 killer, responsible for 17.9 million deaths, or a third of the total each year before the pandemic, and there’s already growing evidence of the outsize impact the coronavirus is having on our long-term health.

Multiple studies suggest that Americans’ collective blood pressures has jumped since the crisis began. According to a December study in the journal Circulation, for example, the average blood pressure among a half-million U.S. adults studied from April to December 2020 went up each month for both of the numbers measured by monitors.

The Centers for Disease Control and Prevention as of this month had logged more than 1 million excess deaths or deaths since the start of the pandemic that are beyond what we would have expected in normal times. While most of those were directly caused by the virus, there were also an additional 30,000 deaths due to ischemic heart disease and nearly 62,000 additional deaths due to hypertensive disease.

When the coronavirus first hit the United States in 2020, doctors were surprised by the heart involvement in cases they saw: professional athletes with signs of myocarditis or hardening of the heart walls; patients dying from their illness with hundreds of tiny clots in major organs; children rushed to emergency rooms with an inflammatory reaction involving cardiac complications.

Many of those presentations turned out to be rare or rarely serious. But they led researchers to an important discovery: that SARS-CoV-2 could directly attack the heart and blood vessels, in addition to the lungs.

Myocarditis has mostly been a transient issue, impacting activity or becoming life-threatening in only a small minority of cases; the clotting is more widespread but something that usually can be controlled with blood thinners; and the pediatric inflammatory syndrome has affected only about 6,400 children out of millions of cases, as of January.

The idea that infections increase cardiovascular risk is not new. It has been documented in cases of influenza and other viruses as well. But in coronavirus, that impact seems “enhanced,” said Antonio Abbate, a professor of cardiology at the VCU Pauley Heart Center. And the early and obvious cases, he said, should serve “as a kind of warning” for the type of longer-term cases we may see into the future.

Indeed, as the months since their infections have turned into years, people who initially had mild or even some asymptomatic coronavirus cases are pouring into cardiology practices across the country.

At Memorial Hermann-Texas Medical Center in Houston, Abhijeet Dhoble, an associate professor of cardiovascular medicine, said they are seeing an increase in arrhythmia, an abnormality in the timing of the heartbeat, and cardiomyopathy, a heart muscle disease. The patients, who previously had covid, range in age from their 30s to 70s and many had no previous heart disease.

“We are seeing the same patterns at university clinics and the hospital,” he said.

Two different processes may be at play, according to David Goff, director of the National Heart, Lung and Blood Institute’s division of cardiovascular sciences. The virus may inflict direct damage to the heart muscle cells, some of which could die, resulting in a weaker heart that does not pump as well. Another possibility is that after causing damage to blood vessels through clots and inflammation, the healing process involves scarring that stiffens vessels throughout the body, increasing the work of the heart.

“It could lead over time to failure of the heart to be able to keep up with extra work,” he explained.

Blood vessels and fatigue

David Systrom, a pulmonary and critical care doctor at Brigham and Women’s Hospital in Boston, said he believes blood vessel damage may be responsible for one of the most common and frustrating symptoms of long covid — fatigue.

Systrom and his colleagues recruited 20 people who were having trouble exercising. Ten had long covid. The other half had not been infected with the virus. He inserted catheters into their veins to provide test information before putting them on stationary bikes and took a number of detailed measurements. The study was published in the journal Chest in January.

In the long covid group, he found that they had normal lung function and at peak exercise, their oxygen levels were normal even as they were short of breath. What was abnormal was that some veins and arteries did not appear to be delivering oxygen efficiently to the muscles.

He theorized this could be due to a malfunction in the body’s autonomic nervous system, which controls involuntary actions such as the rate at which the heart beats, or the widening or narrowing of blood vessels.

“When exercising, it acts like a traffic cop that distributes blood flow to muscles away from organ systems like the kidney and gut that don’t need it. But when that is dysfunctional, what results is inadequate oxygen extraction,” he said. That may lead to the feeling of overwhelming exhaustion that covid long haulers are experiencing.

The overall the message from providers is that “covid by itself is a risk factor for heart disease” like obesity, diabetes, or high blood pressure, according to Saurabh Rajpal, a cardiologist at Ohio State University Wexner Medical Center.

“This is a virus that really knocks people down,” agreed Nicole Bhave, a cardiologist with Michigan Medicine and member of the American College of Cardiology’s science committee. “Even young, healthy people don’t often feel very normal for weeks to months, and it’s a real challenge to distinguish what’s just your body slowly healing versus a new pathological problem.”

“People experiencing what appear to be heart issues should have a “a low threshold for seeing their primary care doctor,” she said.

Heart beats

Unexplained high blood pressure has been a common symptom after covid infection.

Lindsay Polega, 28, an attorney from St. Petersburg, Fla., had never had any medical issues before covid. She had been an all-state swimmer in high school and ran, swam or otherwise exercised an hour or more every day since. But after two bouts with covid, the first in early 2020 and the second in spring 2021, she’s been having what doctors call “hypertensive spikes” that result in shooting pains in her chest that make her shaky and weak. During those incidents, which sometimes occur a few times a day, her blood pressure has gone as high as 210/153 — far above the 120/80, that is considered normal.

One incident happened during a light Pilates class and she had to go to the emergency room. Other times, it has happened while walking. “Sometimes I’ll just be on the couch,” she said.

Each specialist she saw referred her to another — endocrinology, immunology, cardiology, neurology. Finally, she found herself at a long-covid clinic where the doctor theorized the issue may be with her adrenal gland. Scientists have documented that the virus can target the adrenal glands, which produce hormones that help regulate blood pressure among other essential functions. Polega was put on a heavy-duty blood pressure drug called eplerenone that’s typically used in patients after a heart attack, and it has helped to reduce but not eliminate the episodes.

The scariest part for Polega is that women taking eplerenone are cautioned against pregnancy due to research in animals showing low birth weights and other potential dangers. Polega and her boyfriend of six years had recently purchased a house together, and were talking about starting a family soon.

“That’s a big thing to have taken away at my age — my future,” she said.

Of all the symptoms of long covid, among the most baffling have been erratic heart rates and skipped heartbeats with no clear cause.

Tiffany Brakefield, a 36-year-old pharmacy tech from Bonita Springs, Fla., who had covid in June 2020, said the spikes are so unpredictable that she found herself having to sit down on the floor at Walmart during a recent shopping excursion.

“I felt like I was going to fall down, and all I could do was wait for it to calm down on its own,” she said. Her doctors had put her on a heart medication, metoprolol, but it has not helped.

Rick Templeton, a 52-year-old community college instructor in Lynchburg, Va., felt chest tightness along with a racing heart rate, but in his case it disappeared five to six months after his infection in September 2020, and doctors never knew why it happened because his test results were normal.

Rajpal, the cardiologist in Ohio, said a large majority of his post-covid cases are similarly vexing.

“The most common type of long haulers we are seeing have shortness of breath, chest discomfort, and fast heart rate. But when we investigate them for heart disease they come back as normal,” he said.

Goff, the NIH scientist, said the presentation looks similar to a condition known as POTS, or postural orthostatic tachycardia syndrome, in which symptoms such as lightheadedness and heart rate changes are related to reduced blood volume, typically worsened by changing positions. A body of emerging evidence suggests that for many people, it could be a post-viral syndrome.

He said the unstable heart rate for many post-covid patients “can be quite serious and debilitating, and can really interfere with ordinary day-to-day activities.” Doctors can use blood pressure medications to try to stabilize heart rates but because they depress blood pressures at the same time, they can be tricky to use.

Murphy, the Ohio long covid patient, said that when her heart rate soars, which happens several times an hour, she said “it feels like a hamster in my chest.”

Her troubles began on Sept. 5, when she and her teenage daughter tested positive for the virus. Her daughter got over her illness in a few days. Murphy was acutely ill for about three weeks, and many of her symptoms never went away.

The 44-year-old single mom says she’s extraordinarily weak and has trouble with her memory sometimes. Before she was infected, she worked 12-hour days as a day care provider, a waitress and a cashier. Now she’s lucky if she can last three to four hours at her job as a DoorDash driver.

She’s tried to stay active by taking walks but sometimes “when I take steps, it’ll be like stars.” When she saw the cardiologist, she passed out during the stress test on the treadmill.

“I constantly live in fear I’m going to have a heart attack or stroke,” she said.

After all her heart tests came back fine except for her EKG, which showed the jumping heart rate, her doctors referred her to the Cleveland Clinic’s long covid group. She hopes they will help her find answers.