A new study out of Europe has revealed that cases of heart inflammation that required hospitalization were much more common among vaccinated individuals compared to the unvaccinated.
A team of researchers from health agencies in Finland, Denmark, Sweden, and Norway found that rates of myocarditis and pericarditis, two forms of potentially life-threatening heart inflammation, were higher in those who had received one or two doses of either mRNA-based vaccine – Pfizer’s or Moderna’s.
In all, researchers studied a total of 23.1 million records on individuals aged 12 or older between December 2020 and October 2021. In addition to the increased rate overall, the massive study confirmed the chances of developing the heart condition increased with a second dose, which mirrors other data that has been uncovered in recent months.
“Results of this large cohort study indicated that both first and second doses of mRNA vaccines were associated with increased risk of myocarditis and pericarditis. For individuals receiving 2 doses of the same vaccine, risk of myocarditis was highest among young males (aged 16-24 years) after the second dose. These findings are compatible with between 4 and 7 excess events in 28 days per 100 000 vaccinees after BNT162b2, and between 9 and 28 excess events per 100 000 vaccinees after mRNA-1273.
The risks of myocarditis and pericarditis were highest within the first 7 days of being vaccinated, were increased for all combinations of mRNA vaccines, and were more pronounced after the second dose.”
Also mirroring other data, the study confirmed that young people, especially young males, are the ones who are suffering the worst effects of the experimental jab. Young men, aged 16-24 were an astounding 5-15X more likely to be hospitalized with heart inflammation than their unvaccinated peers.
But it isn’t just young men, all age groups across both sexes – except for men over 40 and girls aged 12-15 – experienced a higher rate of heart inflammation post-vaccination when compared to the unvaxxed.
From The Epoch Times, who spoke with one of the study’s main researchers, Dr. Rickard Ljung:
“‘These extra cases among men aged 16–24 correspond to a 5 times increased risk after Comirnaty and 15 times increased risk after Spikevax compared to unvaccinated,’ Dr. Rickard Ljung, a professor and physician at the Swedish Medical Products Agency and one of the principal investigators of the study, told The Epoch Times in an email.
Comirnaty is the brand name for Pfizer’s vaccine while Spikevax is the brand name for Moderna’s jab.
Rates were also higher among the age group for those who received any dose of the Pfizer or Moderna vaccines, both of which utilize mRNA technology. And rates were elevated among vaccinated males of all ages after the first or second dose, except for the first dose of Moderna’s shot for those 40 or older, and females 12- to 15-years-old.”
Although the peer-reviewed study found a direct link between mRNA based vaccines and increased incident rate of heart inflammation, the researchers claimed that the “benefits” of the experimental vaccines still “outweigh the risks of side effects,” because cases of heart inflammation are “very rare,” in a press conference about their findings earlier this month.
However, while overall case numbers may be low in comparison to the raw numbers and thus technically “very rare,” the rate at which individuals are developing this serious condition has increased by a whopping amount. When considering the fact that 5-15X more, otherwise healthy, young men will come down with the condition – especially since the chances of Covid-19 killing them at that age are effectively zero (99.995% recovery rate) – it’s downright criminal for governments across the world to continue pushing mass vaccinations for everyone.
Dr. Peter McCullough, a world-renowned Cardiologist who has been warning about the long-term horror show that is vaccine-induced myocarditis in young people, certainly thinks so. In his expert opinion, the study does anything but give confidence that the benefits of the vaccine outweigh the risks. In “no way” is that the case, he says. Actually, it’s quite the opposite.
“In cardiology we spend our entire career trying to save every bit of heart muscle. We put in stents, we do heart catheterization, we do stress tests, we do CT angiograms. The whole game of cardiology is to preserve heart muscle. Under no circumstances would we accept a vaccine that causes even one person to stay sustain heart damage. Not one. And this idea that ‘oh, we’re going to ask a large number of people to sustain heart damage for some other theoretical benefit for a viral infection,’ which for most is less than a common cold, is untenable. The benefits of the vaccines in no way outweigh the risks.”
It’s also worth pointing out that the new study’s findings could be an indicator as to what is driving the massive spike in the excess death rates in the United States and across the world. Correlating exactly with the rollout of the experimental mRNA Covid-19 vaccines, people have been dying at record-breaking rates, especially millennials, who experienced a jaw-dropping 84% increase in excess deaths (compared to pre-pandemic) in the final four months of 2021.
Establishing the rate of post-vaccination cardiac myocarditis in the 12-15 and 16-17-year-old population in the context of their COVID-19 hospitalization risk is critical for developing a vaccination recommendation framework that balances harms with benefits for this patient demographic. Design, Setting and Participants: Using the Vaccine Adverse Event Reporting System (VAERS), this retrospective epidemiological assessment reviewed reports filed between January 1, 2021, and June 18, 2021, among adolescents ages 12-17 who received mRNA vaccination against COVID-19. Symptom search criteria included the words myocarditis, pericarditis, and myopericarditis to identify children with evidence of cardiac injury. The word troponin was a required element in the laboratory findings. Inclusion criteria were aligned with the CDC working case definition for probable myocarditis. Stratified cardiac adverse event (CAE) rates were reported for age, sex and vaccination dose number. A harm-benefit analysis was conducted using existing literature on COVID-19-related hospitalization risks in this demographic. Main outcome measures: 1) Stratified rates of mRNA vaccine-related myocarditis in adolescents age 12-15 and 16-17; and 2) harm-benefit analysis of vaccine-related CAEs in relation to COVID-19 hospitalization risk. Results: A total of 257 CAEs were identified. Rates per million following dose 2 among males were 162.2 (ages 12-15) and 94.0 (ages 16-17); among females, rates were 13.0 and 13.4 per million, respectively. For boys 12-15 without medical comorbidities receiving their second mRNA vaccination dose, the rate of CAE is 3.7-6.1 times higher than their 120-day COVID-19 hospitalization risk as of August 21, 2021 (7-day hospitalizations 1.5/100k population) and 2.6-4.3-fold higher at times of high weekly hospitalization risk (2.1/100k), such as during January 2021. For boys 16-17 without medical comorbidities, the rate of CAE is currently 2.1-3.5 times higher than their 120-day COVID-19 hospitalization risk, and 1.5-2.5 times higher at times of high weekly COVID-19 hospitalization. Conclusions: Post-vaccination CAE rate was highest in young boys aged 12-15 following dose two. For boys 12-17 without medical comorbidities, the likelihood of post vaccination dose two CAE is 162.2 and 94.0/million respectively. This incidence exceeds their expected 120-day COVID-19 hospitalization rate at both moderate (August 21, 2021 rates) and high COVID-19 hospitalization incidence. Further research into the severity and long-term sequelae of post-vaccination CAE is warranted. Quantification of the benefits of the second vaccination dose and vaccination in addition to natural immunity in this demographic may be indicated to minimize harm.
Millennials Experienced the “Worst-Ever Excess Mortality in History” – An 84% Increase In Deaths After Vaccine Mandates
Dowd, with the assistance of an insurance industry expert, compiled data from the CDC showing that, in just the second half of 2021, the total number of excess deaths for millennials was higher than the number of Americans who died in the entirety of the Vietnam War. Between August and December, there were over 61,000 deaths in this age group, compared to 58,000 over the course of 10 years in Vietnam.
In all, excess death among those who are traditionally the healthiest Americans is up by 84%.
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.
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).
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
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).
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.
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.
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
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.
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
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).
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).
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.
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.
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.
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.
Background: Colchicine is an old drug originally employed for the treatment of inflammatory disorders such as acute gout and familiar Mediterranean fever.
Methods: In the past few decades, colchicine has been at the forefront of the pharmacotherapy of several cardiac diseases, including acute and recurrent pericarditis, coronary artery disease, prevention of atrial fibrillation and heart failure. In this review, we have summarized the current evidence based medicine and guidelines recommendations in the specific context of pericardial syndromes.
Results: Colchicine has been firstly engaged in the treatment of recurrent pericarditis of viral, idiopathic and autoimmune origin. Shortly thereafter colchicine use has been expanded to the primary prevention of recurrences in patients with a first episode of pericarditis depicting similarly good results. The acquisition of high quality scientific data in the course of time from prospective randomized placebo-controlled trials and metanalyses have established colchicine as first line treatment option in acute and recurrent pericarditis, on top of the conventional treatment. The only concerns related to the use of colchicine are the side effects (mainly gastrointestinal intolerance) which although generally not serious, may account for treatment withdrawal in some cases.
Conclusion: Colchicine has been established as a first line medication in the treatment of acute (first episode) and recurrent pericarditis on top of the conventional treatment as well as for the prevention of postpericardiotomy syndrome. It depicts a good safety profile with gastrointestinal intolerance being the most common side effect.
The COVID-19 pandemic is a highly contagious viral illness which conventionally manifests primarily with respiratory symptoms. We report a case whose first manifestation of COVID-19 was pericarditis, in the absence of respiratory symptoms, without any serious complications. Cardiac involvement in various forms is possible in COVID-19. We present a case where pericarditis, in the absence of the classic COVID-19 signs or symptoms, is the only evident manifestation of the disease. This case highlights an atypical presentation of COVID-19 and the need for a high index of suspicion to allow early diagnosis and limit spread by isolation.
This article is made freely available for use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.https://bmj.com/coronavirus/usage
The global COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2, an enveloped single-stranded RNA virus of zoonotic origin. Transmission is mainly by aerosolised droplet contact, although surface fomite contact and faecal transmission are reported. Symptoms of coronavirus include high-grade fever, severe cough and breathlessness. Cytokine induction causes heavy neutrophilia in the alveoli, with capillaritis, fibrin deposition and thick mucositis causing respiratory failure, acute lung injury and death. Conversely approximately one in eight patients are estimated to have an entirely benign course, transmitting the virus with no clinical manifestation of the disease.1 2 Chest pain in COVID-19 may have cardiac causes, including acute coronary syndrome, pericarditis and myocarditis.3 We present the first described case of acute pericarditis in the absence of initial respiratory symptoms secondary to COVID-19.
A 66-year-old farmer was admitted with 1-day history of acute-onset severe pleuritic chest pain, with four episodes lasting 10–15 min. The pain was worse when lying flat and relieved by leaning forward. He had no sweating nor fever. His history includes Crohn’s disease, hypertension and benign prostatic hyperplasia. His medications were esomeprazole, ramipril and tamsulosin. He had a 40 pack-year smoking history and a significant familial premature coronary disease. His vaccination schedule was up to date, and he had not travelled recently. On examination his temperature was 36.9°C, blood pressure was 134/83 mm Hg, heart rate was 86 beats/min, respiratory rate was 16 breaths/min and an O2 saturation of 99% on ambient air. His general, cardiovascular and respiratory examinations were normal.
Full blood count, urea and electrolytes, coagulation profile, and liver function tests were normal. His C reactive protein (CRP) was 7 mg/L (normal <5 mg/L). High sensitivity cardiac troponin T (hs-cTnT) on admission and at 6 hours were 10 ng/L and 13 ng/L, respectively (normal <14 ng/L). His ECG showed ST segment elevation in most leads with PR interval depression, and his chest X-ray (CXR) confirmed clear lungs with no abnormality (figure 1). Transthoracic echocardiogram (TTE) confirmed normal structure and function, although his pericardium was echo bright with no pericardial effusion (figure 2). CT of the thorax, abdomen and pelvis was normal.
Transthoracic echocardiogram showing brightened pericardium (white arrows) with no effusion.
Serum, nasopharyngeal and oropharyngeal swab specimen samples were sent for aetiological viruses associated with pericarditis. However, the patient presented in February 2020, which was early in the chronology of COVID-19 in Ireland and he did not have routine COVID-19 screening swabs. Complement levels, erythrocyte sedimentation rate and connective tissue screens were negative. Nucleic acid amplification tests for influenza A and B were negative. Cardiac MRI (cMRI) with adenosine stress perfusion showed a structurally normal heart with no effusion, fibrosis, infarction or infiltration. No inducible perfusion defects were evident during adenosine stress. His pericardium appeared mildly thickened (figure 3).
Cardiac MRI of the patient with perfusion showing normal left ventricle muscle (black arrows). The pericardium, pointed by white arrows, shows mild thickening (bold white) with no effusion.
Differential diagnoses included myocarditis, acute coronary syndrome, pericarditis or pleuritis.
A diagnosis of pericarditis was made based on typical chest pain, ECG presentation and TTE. He was started on oral colchicine two times per day for 2 weeks and was discharged on day 4.
Outcome and follow-up
The patient was readmitted on day 6 with recurrence of intermittent pleuritic chest pain and dry cough. Vital signs, physical examination and blood tests were normal. CXR and ECG remained unchanged. Viral serology was negative for routine viruses associated with pericarditis. A COVID-19 viral PCR nasopharyngeal swab was positive.
The public health team was notified and the patient was isolated. On day 8 he developed upper respiratory tract symptoms with peak temperature of 38.7°C. Lymphopaenia (0.3×109, normal >1×109/L) with normal interleukin-6 (5.77, normal 0.09–7.26 pg/mL), CRP and hs-cTnT were seen. Blood culture showed no growth, and serial CXR remained normal. He recovered with symptomatic treatment and oral colchicines and was discharged on day 12.
COVID-19 has numerous adverse effects on the cardiovascular system. Cardiac injury with troponin leak is associated with increased mortality in COVID-19, and its clinical and radiographic features are difficult to distinguish from those of heart failure.4–6 One reported COVID-19 case with upper respiratory tract symptoms had haemorrhagic pericardial effusion with tamponade.7 To our knowledge this is the first case where COVID-19 presents as pericarditis, in the absence of evident respiratory or myocardial involvement.
Acute pericarditis is the most common disease of the pericardium and is responsible for 0.2% of chest pain-related hospitalisations. Conversely 40%–85% of pericarditis cases are of unknown aetiology, probably due to difficulty in obtaining diagnostic pericardial samples. It is commonly seen in viral infections, including coxsackie, enterovirus, herpes simplex, cytomegalovirus, H1N1, respiratory syncytial virus, parvovirus B19, influenza, varicella, HIV, rubella, echovirus, and hepatitis B and C, although the viruses responsible in a given patient may be different genotypes of the same virus or different coexistent viruses.8 9
In this patient respiratory swabs were initially negative, and viraemia first manifested with dry pericarditic symptoms, with a later diagnosis of COVID-19. Defining the underlying causative virus is not always possible. Serological tests are only suggestive of a diagnosis of pericarditis and may yield false negative results. Pericardial inflammation may prompt symptoms, yet may precede the generation of an observable pericardial effusion. TTE is recommended to exclude significant effusion, although the absence of fluid does not rule out active pericarditis. cMRI can describe pericardial thickening or small effusions, which are not appreciated on TTE, assess for myocarditis on T2-weighted imaging, define pericardial inflammation on late gadolinium phase and quantify systolic function.10 Pericardiocentesis is the gold standard for definition of the underlying cause, providing a sufficient depth of fluid at a favourable angle is seen on TTE, although this carries associated risk of serious cardiac injury and a clinical diagnosis may be made if other supportive features are present.
Acute pericarditis is usually self-limiting, although it recurs in up to 30% of cases. Most patients recover in 2–4 weeks with supportive measures, which would conventionally include non-steroidal anti-inflammatory drugs (NSAIDs), colchicines and treating the causative disease. Applying this to a patient with COVID-19 requires balancing this conventional approach with an emerging understanding of pharmacotherapy in COVID-19. Colchicine inhibits microtubule, cell adhesion molecule and inflammasome activity, and is of use in preventing relapse in pericarditis at first presentation.11 It is being trialled as a potential therapeutic anticytokine agent in COVID-19 in Italy, with one report of its use being associated with improvement.12 Conversely the use of NSAIDs in COVID-19 may be harmful, with previously recognised increased risks of stroke and myocardial infarction (MI) with NSAIDs in acute respiratory infections raising concerns. No effective respiratory benefit has been seen with glucocorticoid use in COVID-19, although their use in pericarditis may promote relapse.13 14
Currently, our understanding of the transmission dynamics and the spectrum of clinical illness of COVID-19 is limited. Cardiac involvement with various ECG presentations is possible and clinicians all across the globe need to be aware of this possibility. This case highlights the importance of recognising COVID-19 infection with atypical clinical presentations such as pericarditis and non-specific ECG changes, and coordination with healthcare team regarding prompt isolation to decrease the risk of transmission of the virus and if any need of early hospitalisation. This case report is helpful in treating patients with this unique clinical presentation.
I woke up one day and I had a nagging pain in the center of my chest, which I never had or felt before, sharp like a knife and pressure on top of it as well. It was a constant nagging pain. It was relieving when I was sitting forward and back worsened as I was lying down in the bed. I felt more weak that day and had no energy. Then pain got a bit worse at midday and my wife advised me to visit my doctor -general practitioner as a felt weak. After my doctor saw me, he advised me to go to the hospital and get myself check out to make sure I am not having a heart attack. I and my wife got very nervous. We came urgent to hospital emergency where a nurse examined me first, followed by a doctor and suggested they don’t think that I am having a heart attack. He referred me to heart expert, who suggested that I have to be admitted in the hospital for more tests. They kept me for three days and all my tests like chest and body scans and bloods suggested that I have inflammation around the layers of heart. I was given some medication and discharged home that it will get better in a few days. I went home, the pain was there, it didn’t went completely but improved slightly. It was worse with lying down in the bed. It wasn’t going away despite me doing all what I was told for next few days. I came back to emergency department in 1st march as the pain wasn’t settling at all with the medication. I went through all this process again. I was isolated, swabbed my nose for this new virus-COVID-19. I did not had any sick contact or any other viral contact. I was nervous, and the result came positive. I was kept in separate part of hospital with no direct visitors to me and my family called me on the phone. I thought I am going to die but all the doctors and nurses reassured me. I developed slight cough and flu like illness for 2 days and then I got better next few days and I came home. I was told to follow strict isolation and precautions. No issues since discharge feeling very well. It’s an unpleasant experience to be part of virus and I thought I won’t make it as there was uncertainty about future events. I am greatly thankful to all the team who were involved in my care.
Pericarditis is a potential presentation of COVID-19.
COVID-19 can have an atypical presentation with non-respiratory symptoms.
Recognition of an atypical symptom of COVID-19 allows for early isolation and limits the spread.
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Background—The most troublesome complication of acute pericarditis is recurrent episodes of pericardial inflammation, occurring in 15% to 32% of cases. The cause of the recurrence is usually unknown, although in some cases it may be traced to viral infection or may be a consequence of coronary artery bypass grafting. The optimal method for prevention has not been fully established; accepted modalities include nonsteroidal anti-inflammatory drugs, corticosteroids, immunosuppressive agents, and pericardiectomy.
Methods and Results—Based on the proven efficacy of colchicine therapy for familial Mediterranean fever (recurrent polyserositis), several small studies have used colchicine successfully to prevent recurrence of acute pericarditis after failure of conventional treatment. Recently, we reported the results from the largest multicenter international study on 51 patients who were treated with colchicine to prevent further relapses and who were followed up for ≤10 years.
Conclusions—In light of new trial data that have accumulated in the past decade, we review the evidence for the efficacy and safety of colchicine for the prevention of recurrent episodes of pericarditis. Clinical and personal experience shows that colchicine may be an extremely promising adjunct to conventional treatment and may ultimately serve as the initial mode of treatment, especially in idiopathic cases.
Acute inflammation of the pericardium is usually of idiopathic etiology, but it may also be secondary to systemic infection, acute myocardial infarction, cardiac contusion, and autoimmune diseases.1
The most troublesome complication of acute pericarditis is the development of recurrent episodes of pericardial inflammation, occurring in 15% to 32% of cases.2345 Recurrent pericarditis is, in most cases, idiopathic. The pathophysiological process may involve the immune system6,7: high titers of anti-myocardial antibodies have been found in post–open heart surgery patients with acute pericarditis. The optimal method for preventing recurrences has not been established. Therapeutic modalities are nonspecific and include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, immunosuppressive agents, and pericardiectomy.18 Relapses may also occur during reduction of drug doses (incessant pericarditis) or at varying intervals after discontinuation of treatment (recurrent pericarditis).9 Because treatment is often difficult and recurrences may occur over a period of many years,10 constant efforts are being directed toward establishing better means for prevention. In light of recent trial data, we will review the evidence supporting the use of colchicine in preventing recurrent episodes of pericarditis.
On the basis of proven efficacy of colchicine in preventing relapses of systemic inflammatory processes in familial Mediterranean fever (recurrent polyserositis),1112 Rodriguez de la Serna and colleagues13 suggested in 1987 that colchicine be used to prevent recurrences of acute pericarditis. They reported on 3 patients who had recurrent pericarditis (2 idiopathic and 1 with systemic lupus erythematosus), despite adequate treatment with corticosteroids. All were treated with colchicine (1 mg/d) with tapering of the corticosteroids within 2 months. There were no relapses throughout the follow-up period of 15 to 35 months.
In a later prospective study, Guindo and colleagues14 reported on 9 patients (5 idiopathic, 2 post–open heart surgery, 1 with Dressler’s syndrome, and 1 with systemic lupus erythematosus) in whom NSAIDs and corticosteroids failed to prevent relapses of pericarditis (mean of 4.3 episodes per patient). All were treated with combined prednisone (20 to 60 mg/d), which was tapered and discontinued within 6 weeks, and colchicine (1 mg/d). Chest pain was effectively relieved, and no recurrences of pericarditis were noted within a 10- to 54-month follow-up period.
Adler and coworkers10 reported on 8 patients with recurrent pericarditis (5 idiopathic, 2 post–open heart surgery, 1 post chest trauma) who had not responded to NSAIDs (6 patients), corticosteroids (7 patients), and pericardiocentesis (3 patients). All responded to colchicine (1 mg/d) and corticosteroids. The corticosteroids were discontinued within 2 to 6 months, and no recurrences were noted during the 18 to 34 months of follow-up. This result contrasts with a total of 26 relapses in these 8 patients before the introduction of colchicine. Four patients in whom colchicine had been withdrawn because of noncompliance or mild gastrointestinal side effects experienced a relapse within 1 to 12 weeks. With reinstitution of colchicine therapy, they remained symptom-free for the 15 to 24 months of follow-up.
Millaire and coworkers15 reported on 19 patients who had recurrent pericarditis and were treated with colchicine (loading dose of 3 mg/d, reduced to 1 mg/d). Fourteen had no recurrences during a follow-up period of 32 to 44 months. In 4 others, relapses were successfully treated with NSAIDs, and these patients remained symptom-free for an additional 11 to 37 months. Only 1 patient had multiple relapses and needed corticosteroids. The authors concluded that colchicine was an effective alternative therapy for recurrent pericarditis and might even replace corticosteroids. In another report by Adler et al,16 colchicine totally prevented relapses in 56% of patients with previous episodes (range, 2 to 15 attacks) in a long-term follow-up (mean, 36 months per patient) study, and when relapses did occur, they were usually mild and easily controlled without steroids. These researchers suggested that colchicine might even serve as the initial mode of therapy for recurrent pericarditis, because most of the patients who experienced relapses after the institution of colchicine or its withdrawal were those who had previously been treated with corticosteroids.16 Indeed, several studies have found that corticosteroids may have severe side effects and lead to new recurrences of pericarditis or prolong disease duration.17181920 Thus, colchicine may also have a role in facilitating their tapering-off process.9 Still, some authors doubt the efficacy of colchicine because a double-blind, controlled study on the subject is difficult to perform.21 It was for this reason that Fowler and Harbin22 examined the natural history of recurrent pericarditis to determine the frequency of spontaneous remissions. Of the 31 patients included in their study, only 8 had a remission period that exceeded 1 year; in 5 of the 8, remission exceeded 2 years.
A partial answer to these doubts may be found in the largest multicenter study on recurrent pericarditis and colchicine published to date.23 Fifty-one affected patients (36 men and 15 women; mean±SD age, 40.8±18.7 years) who were treated with colchicine to prevent further relapses were followed up for ≤10 years (range, 6 to 128 months; mean, 36.0 months). The pericarditis was idiopathic in 33 patients and secondary in 18. Despite treatment with NSAIDs (n=47), corticosteroids (n=29), pericardiocentesis (n=8), or some combination thereof, 187 recurrences (mean, 3.58±3.64; range, 2 to 15) were noted before colchicine therapy was initiated, with a mean interval between crises of 2.0 months (range, 0.5 to 19 months). During 1004 patient-months of colchicine treatment, only 7 of 51 patients (13.7%) presented with new recurrences. Colchicine was discontinued in 39 patients, and 14 of them (35.8%) experienced relapses. These recurrences were generally minor and were effectively controlled in all patients by the reinstitution of colchicine therapy, sometimes with a dose adjustment of the drug (≤2 mg/d). Gastrointestinal side effects were mild (diarrhea and nausea) and resolved in all patients. During the 2333 patient-months of follow-up, 31 patients (60.7%) remained recurrence-free. Comparison of the symptom-free periods before and after colchicine treatment yielded significant statistical differences (3.1±3.3 versus 43.0±35.0 months, P<0.0001). The authors concluded that colchicine was effective and safe for the long-term prevention of recurrent pericarditis.
The exact mechanism whereby colchicine prevents recurrences of pericarditis is still not fully understood. Colchicine has been used for several centuries as an anti-inflammatory agent for acute arthritis and is the most specific known treatment for acute attacks of gout. Colchicine binds to tubulin, blocks mitosis,9 and inhibits a variety of functions of polymorphonuclear leukocytes both in vivo and in vitro.24 Colchicine also interferes with the transcellular movement of collagen.25 The close proximity of lymphoid components and fibroblasts at inflammatory sites and the production of lymphokines, which influence fibroblast chemotaxis, proliferation, and protein synthesis, are now well recognized.26 Thus, colchicine may reduce immunopathic antifibroblastic properties. The peak concentration of colchicine in white blood cells may be ≥16 times the peak concentration in plasma. This preferential concentration of colchicine in lymphocytes is related to its observed therapeutic effect.27
Cumulative anecdotal evidence indicates that colchicine may also be effective in the treatment of the initial episodes of acute pericarditis. Millaire and Durlaux,28 in a study of 19 patients, described the efficacy of colchicine for the first episode of acute pericarditis, especially when it was idiopathic, viral, or post–open heart surgery. Colchicine effectively controlled the acute phase of pericarditis in almost all cases. Only two relapses were noted in a mean follow-up period of 5 months (range, 1 to 12 months), one due to discontinuation of treatment after 8 days and the other due to noncompliance.
Recently, we examined the usefulness of colchicine for the treatment of large pericardial effusions as complications of idiopathic pericarditis.29 Colchicine (1 mg/d) was administered to two patients (26 and 2 years old) with large acute or chronic pericardial effusions who did not respond well to therapy with NSAIDs, corticosteroids, and pericardiocentesis. Response was immediate and dramatic in both cases, with disappearance of the pericardial effusion on echocardiography. Neither patient suffered a relapse during the respective 24 and 6 months of follow-up.
In addition to its apparently greater efficacy compared with corticosteroids,916 colchicine may also have a sparing effect on steroids, which have severe systemic side effects over time and may prolong disease duration.17181920 Furthermore, immunosuppressive drugs and pericardiectomy are generally not appropriate and may even be life threatening,21 whereas colchicine is usually well tolerated, with only minor side effects. During a total of 1004 patient-months of colchicine treatment (mean, 12 months per patient), temporary discontinuation of the drug or a reduction of its dose was needed in only 7 of 51 patients (13.7%).23 This was due to mild gastrointestinal side effects (diarrhea and nausea) in all cases, which are the common drawbacks of colchicine therapy. Drug toxicity with respect to long-term administration of colchicine might be estimated from familial Mediterranean fever or gout patients. Azoospermia and chromosomal abnormalities have been reported with long-term treatment,30 but these findings are debatable.
In conclusion, colchicine seems to be an effective and safe agent for the prevention of recurrent episodes of pericarditis. Colchicine is an extremely promising adjunct to the conventional treatment of recurrent pericarditis and may ultimately serve as the initial mode of treatment, especially in idiopathic cases. Considering that recurrent pericarditis is not life threatening and that long-term treatment is aimed at improving the quality of life, we suggest that corticosteroids should be limited to very severe cases. Milder cases may initially be treated with colchicine as well as with NSAIDs (ibuprofen). The recommended dose of colchicine according to most studies is 1 mg/d for at least 1 year, with a gradual tapering off. The need for a loading dose of 2 to 3 mg/d at the beginning of treatment is unclear. The drug is well tolerated. Gastrointestinal side effects develop in only a small proportion of patients, are usually minor, and do not require discontinuation of treatment in most cases.
Despite the promising data on the efficacy and safety of colchicine for recurrent pericarditis that have accumulated in the past decade, large, controlled, prospective studies are required to provide definitive answers on the subject.
We thank Gloria Ginzach, Marian Propp, and Charlotte Sacks for their editorial and secretarial assistance.
Correspondence to Y. Adler, MD, Department of Cardiology, Rabin Medical Center, Beilinson Campus, Petah Tiqva, 49100, Israel.
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Massive study shows a long-term, substantial rise in risk of cardiovascular disease, including heart attack and stroke, after a SARS-CoV-2 infection.
Even a mild case of COVID-19 can increase a person’s risk of cardiovascular problems for at least a year after diagnosis, a new study1 shows. Researchers found that rates of many conditions, such as heart failure and stroke, were substantially higher in people who had recovered from COVID-19 than in similar people who hadn’t had the disease.
What’s more, the risk was elevated even for those who were under 65 years of age and lacked risk factors, such as obesity or diabetes.
“It doesn’t matter if you are young or old, it doesn’t matter if you smoked, or you didn’t,” says study co-author Ziyad Al-Aly at Washington University in St. Louis, Missouri, and the chief of research and development for the Veterans Affairs (VA) St. Louis Health Care System. “The risk was there.”
Al-Aly and his colleagues based their research on an extensive health-record database curated by the United States Department of Veterans Affairs. The researchers compared more than 150,000 veterans who survived for at least 30 days after contracting COVID-19 with two groups of uninfected people: a group of more than five million people who used the VA medical system during the pandemic, and a similarly sized group that used the system in 2017, before SARS-CoV-2 was circulating.
People who had recovered from COVID-19 showed stark increases in 20 cardiovascular problems over the year after infection. For example, they were 52% more likely to have had a stroke than the contemporary control group, meaning that, out of every 1,000 people studied, there were around 4 more people in the COVID-19 group than in the control group who experienced stroke.
The risk of heart failure increased by 72%, or around 12 more people in the COVID-19 group per 1,000 studied. Hospitalization increased the likelihood of future cardiovascular complications, but even people who avoided hospitalization were at higher risk for many conditions.
“I am actually surprised by these findings that cardiovascular complications of COVID can last so long,” Hossein Ardehali, a cardiologist at Northwestern University in Chicago, Illinois, wrote in an e-mail to Nature. Because severe disease increased the risk of complications much more than mild disease, Ardehali wrote, “it is important that those who are not vaccinated get their vaccine immediately”.COVID’s cardiac connection
Ardehali cautions that the study’s observational nature comes with some limitations. For example, people in the contemporary control group weren’t tested for COVID-19, so it’s possible that some of them actually had mild infections. And because the authors considered only VA patients — a group that’s predominantly white and male — their results might not translate to all populations.
Ardehali and Al-Aly agree that health-care providers around the world should be prepared to address an increase in cardiovascular conditions. But with high COVID-19 case counts still straining medical resources, Al-Aly worries that health authorities will delay preparing for the pandemic’s aftermath for too long. “We collectively dropped the ball on COVID,” he said. “And I feel we’re about to drop the ball on long COVID.”
Xie, Y., Xu, E., Bowe, B. & Al-Aly, Z. Nature Med. https://www.nature.com/articles/s41591-022-01689-3 (2022).PubMedArticleGoogle Scholar
Question What are the findings on cardiac imaging in children with myocarditis after COVID-19 vaccination?
Findings In this case series of 15 children who were hospitalized with myocarditis after receipt of the BNT162b2 messenger RNA COVID-19 vaccine for 1 to 5 days, boys were most often affected after the second vaccine dose, 3 patients had ventricular systolic dysfunction, and 12 patients had late gadolinium enhancement on cardiac magnetic resonance imaging. There was no mortality, and all but 1 patient had normal echocardiogram results on follow-up 1 to 13 days after discharge.
Meaning COVID-19 vaccine-associated myocarditis may have a benign short-term course in children; however, the long-term risks remain unknown.Abstract
Importance The BNT162b2 (Pfizer-BioNTech) messenger RNA COVID-19 vaccine was authorized on May 10, 2021, for emergency use in children aged 12 years and older. Initial reports showed that the vaccine was well tolerated without serious adverse events; however, cases of myocarditis have been reported since approval.
Objective To review results of comprehensive cardiac imaging in children with myocarditis after COVID-19 vaccine.
Design, Setting, and Participants This study was a case series of children younger than 19 years hospitalized with myocarditis within 30 days of BNT162b2 messenger RNA COVID-19 vaccine. The setting was a single-center pediatric referral facility, and admissions occurred between May 1 and July 15, 2021.
Main Outcomes and Measures All patients underwent cardiac evaluation including an electrocardiogram, echocardiogram, and cardiac magnetic resonance imaging.
Results Fifteen patients (14 male patients [93%]; median age, 15 years [range, 12-18 years]) were hospitalized for management of myocarditis after receiving the BNT162b2 (Pfizer) vaccine. Symptoms started 1 to 6 days after receipt of the vaccine and included chest pain in 15 patients (100%), fever in 10 patients (67%), myalgia in 8 patients (53%), and headache in 6 patients (40%). Troponin levels were elevated in all patients at admission (median, 0.25 ng/mL [range, 0.08-3.15 ng/mL]) and peaked 0.1 to 2.3 days after admission. By echocardiographic examination, decreased left ventricular (LV) ejection fraction (EF) was present in 3 patients (20%), and abnormal global longitudinal or circumferential strain was present in 5 patients (33%). No patient had a pericardial effusion. Cardiac magnetic resonance imaging findings were consistent with myocarditis in 13 patients (87%) including late gadolinium enhancement in 12 patients (80%), regional hyperintensity on T2-weighted imaging in 2 patients (13%), elevated extracellular volume fraction in 3 patients (20%), and elevated LV global native T1 in 2 patients (20%). No patient required intensive care unit admission, and median hospital length of stay was 2 days (range 1-5). At follow-up 1 to 13 days after hospital discharge, 11 patients (73%) had resolution of symptoms. One patient (7%) had persistent borderline low LV systolic function on echocardiogram (EF 54%). Troponin levels remained mildly elevated in 3 patients (20%). One patient (7%) had nonsustained ventricular tachycardia on ambulatory monitor.
Conclusions and Relevance In this small case series study, myocarditis was diagnosed in children after COVID-19 vaccination, most commonly in boys after the second dose. In this case series, in short-term follow-up, patients were mildly affected. The long-term risks associated with postvaccination myocarditis remain unknown. Larger studies with longer follow-up are needed to inform recommendations for COVID-19 vaccination in this population.Introduction
SARS-CoV-2 was first identified in China and evolved rapidly to a global pandemic. Vaccines to prevent SARS-CoV-2 infection are the current standard approach for curbing the pandemic. In the US, the BNT162b2 messenger RNA (mRNA) (Pfizer-BioNTech), mRNA-1273 (Moderna), and Ad26.COV2.S (Janssen) vaccines were granted emergency use authorization for adults. On May 10, 2021, the emergency use authorization for the BNT162b2 vaccine was extended to children aged 12 years and older.1
Myocarditis has been reported as a rare complication of vaccination against other viruses.2 It was not reported in the initial messenger RNA COVID-19 vaccine trials, although the ability to detect rare events was limited by sample size. Since the emergency use authorization, myocarditis in adolescents and young adults after COVID-19 vaccine has been reported.3–5 In this series, we detail the occurrence of myocarditis after COVID-19 vaccination in an adolescent population, including comprehensive cardiac imaging evaluation and follow-up.MethodsPopulation
This case series included all patients younger than 19 years admitted at our center with acute myocarditis after COVID-19 vaccination. Myocarditis was defined as chest pain and an elevated troponin level in the absence of an alternative diagnosis. The institutional review board at Boston Children’s Hospital approved this study and granted an exemption from informed consent owing to use of deidentified data and the requirements of 45 CFR §46. This study followed the reporting guideline for case series.Data Collection and Definitions
Clinical data elements including demographic characteristics, laboratory values, and hospital course were collected from the electronic medical record. Patients’ race and ethnicity were self-reported by patients or parents according to the US Census categories6 and were collected because of their known association with COVID-19–related illnesses. Elevated troponin T level was defined as a troponin value greater than 0.01 ng/mL. Cardiac evaluation for all patients included electrocardiogram (ECG), echocardiogram, and cardiac magnetic resonance (CMR) imaging. Ventricular systolic dysfunction was defined as a left ventricular (LV) ejection fraction equal to or greater than 55% on echocardiogram or CMR results. Echocardiographic peak global longitudinal strain was measured from an apical 4-chamber view and peak global circumferential strain from a parasternal short-axis view at the midpapillary level using software (Tom Tec Image Arena, version 4.6; TOMTEC). Strain values were considered abnormal if the z score was less than or equal to −2 for age. Diastolic dysfunction was defined as a z score less than or equal to −2 for age, for septal e′ tissue Doppler, LV free wall e′, or the E/e′ ratio. CMR assessment included LV ejection fraction, T2-weighted myocardial imaging, LV global native T1, LV global T2, extracellular volume fraction, and late gadolinium enhancement (LGE).Statistical Analysis
Descriptive statistics were calculated for all study variables. Quantitative variables were summarized as median and range and categorical variables as frequencies and percentages.Results
Fifteen patients were admitted at the Department of Cardiology, Boston Children’s Hospital for management of myocarditis after COVID-19 vaccination between May 1 and July 15, 2021. The median age was 15 years (range, 12-18 years), and most patients were male (n = 14 [93%]). Patients self-identified as non-Hispanic White (n = 8 [53%]), Hispanic White (n = 2 [15%]), other Hispanic (n = 1 [8%]), other non-Hispanic (n = 1 [8%]), and unknown (n = 3 [20%]) (Table). All patients received the BNT162b2 mRNA vaccine. Symptoms occurred after the second dose of the vaccine in all but 1 case. No patients had a known prior COVID-19 infection, although 1 had reactive SARS-CoV-2 antibodies to the nucleocapsid protein.
Chest pain in 15 of 15 patients (100%) started at median 3 days (range, 1-6 days) after receiving the vaccine and lasted 1 to 9 days. Other symptoms included fever in 10 patients (67%), myalgia in 8 patients (53%), and headache in 6 patients (40%). Seven patients (47%) were treated with intravenous immunoglobulins (2 g/kg) and methylprednisolone (1 mg/kg/dose twice a day, transitioned to prednisone at time of discharge). Hospital length of stay was a median of 2 days (range, 1-5 days), and no patients required intensive care unit admission.Troponin
Troponin levels were elevated in all patients at admission (median, 0.25 ng/mL [range, 0.08-3.15 ng/mL]) and peaked 0.1 to 2.3 days after admission (Table). At the time of discharge, the troponin level had substantially decreased but remained elevated in all patients (Figure 1).Echocardiogram
On admission echocardiogram, 3 patients (20%) had global LV systolic ventricular dysfunction (EF 44%, 49%, and 53%), one of whom also had regional wall motion abnormality at the apex. Two patients (13%) with systolic dysfunction had abnormal diastolic function indices, and 1 patient (7%) with borderline EF (55%) had evidence of diastolic dysfunction. Five patients (33%) had abnormal global longitudinal or global circumferential strain (Figure 2; eFigure 1 and eTable in the Supplement). No patients had a coronary artery aneurysm or pericardial effusion.Electrocardiogram
The most frequent finding was diffuse ST-segment elevation consistent with pericarditis, present on admission in 6 patients (40%), and at some time during hospital admission in 8 patients (53%). Four additional patients had nonspecific ST segment changes. One patient (normal systolic and diastolic ventricular function; LGE on CMR) had nonsustained ventricular tachycardia during hospital admission. ST-T wave changes persisted at time of hospital discharge in 9 patients (69%). No patient had PR interval, QRS duration, or QTc duration prolongation.Cardiac Magnetic Resonance
CMR imaging was performed in all patients 1 to 7 days after the onset of symptoms. Systolic LV dysfunction was present in 3 patients (25%). Findings consistent with myocarditis were found in 13 patients (87%). LGE was present in 12 patients, and most often found in the inferolateral (n = 3) and anterolateral (n = 4) regions (eTable and eFigure 2 in the Supplement). The extracellular volume fraction was borderline elevated (28%-30%) in 4 patients (27%) and elevated (>30%) in 3 patients (25%). LV global native T1 was borderline elevated (1080-1100 milliseconds) in 2 patients and elevated (>1100 milliseconds) in 2 patients. Two patients had regional hyperintensity on T2-weighted imaging. LV global T2 was borderline elevated (56-60 milliseconds) in 1 patient.Follow-up
Follow-up information after hospital discharge was available for all patients (virtual visit in 1 patient; in-person with testing in 14 patients) and occurred 1 to 13 days after discharge. Four patients (27%) were asymptomatic with normal troponin level, ECG, and echocardiogram results.
Four patients (27%) had persistent symptoms, including fatigue in 3 patients (25%) and continued chest pain in 1 patient (7%). None of the patients with persistent symptoms had decreased EF at time of initial presentation (1 with abnormal strain) and 3 patients (75%) had abnormal CMR results with LGE.
One asymptomatic patient (7%) had persistent borderline low LV EF (54%), reduced circumferential strain (z score, −2.3), and reduced lateral e′ velocity (z score, −2.8) measured by echocardiogram at 8 days after discharge; all other patients had normal echocardiogram results. Ventricular systolic function recovered (EF>55%) in 2 to 11 days (Figure 1).
ECG changes persisted in 4 patients (33%) and included nonspecific ST-T wave changes in 4 patients (33%) or new T-wave inversion in 3 patients (20%). One patient (7%) with nonsustained ventricular tachycardia during hospital admission had recurrence of nonsustained ventricular tachycardia on 6 days of ambulatory ECG monitoring, despite initiation of β-blocker therapy.
Troponin levels remained mildly elevated at follow-up in 3 patients (20%) (Figure 1). One patient (7%) with a persistently elevated troponin level (0.05 ng/mL) had continuing fatigue. All patients with persistently elevated troponin levels had had prior abnormalities on CMR (2 patients with LGE, 1 patient with elevated extracellular volume fraction).Discussion
In this early experience of 15 cases, myocarditis typically occurred in male patients after the second dose of the COVID-19 vaccine. All patients in this series had a benign course; none required intensive care unit admission and all were discharged alive from the hospital within 5 days. LV systolic function at presentation was normal in most patients and normalized within a few days in all but 1 patient who had persistent borderline low LV function. This finding differs from other forms of myocarditis in which LV systolic dysfunction and arrhythmias are more common, with 50% of children requiring intensive care unit admission, a mean hospital length of stay of 14.4 days, and a mortality rate of 7.8%.7–9
Although vaccine-associated cases of myocarditis to date have had uncomplicated short-term course, the long-term prognosis remains unclear. Of note, CMR LGE was a frequent finding at time of diagnosis. In this clinical setting, LGE reflects an increased volume of distribution of the gadolinium-based contrast agent in the affected region likely related to myocyte necrosis and/or extracellular edema. In nonvaccine-associated myocarditis, the presence of LGE is associated with increased risk for adverse cardiovascular events during follow-up.10–12 Thus, longitudinal studies of patients with myocarditis after COVID-19 vaccine will be important to better understand long-term risks.
To date, there have been 1226 reports of myocarditis after messenger RNA vaccination to the Vaccine Adverse Event Reporting System (VAERS), including 687 in persons aged less than 30 years.13 Crude reporting rates using vaccine administration data estimates the highest rate among male individuals aged 12 to 17 years (62.8 cases per million), similar to our observations. Despite the risks of myocarditis associated with vaccination, the benefits of vaccination likely outweigh risks in children and adolescents. It is estimated that COVID-19 vaccination in males aged 12 to 29 years can prevent 11 000 COVID-19 cases, 560 hospitalizations, 138 intensive care unit admissions, and 6 deaths compared with 39 to 47 expected myocarditis cases.Limitations
This study has limitations. Limitations to this series include the lack of COVID-19 vaccine administration data, which does not permit calculation of incidence or identification of risk factors for myocarditis. Mild cases may have been missed due to the novelty of this complication and the lack of routine screening.Conclusions
Myocarditis may be a rare complication after COVID-19 vaccination in patients aged less than 19 years. In this case series study, the short-term clinical course was mild in most patients; however, the long-term risks remain unknown. Risks and benefits of COVID-19 vaccination must be considered to guide recommendations for vaccination in this population.Back to topArticle Information
The cardiovascular complications of acute coronavirus disease 2019 (COVID-19) are well described, but the post-acute cardiovascular manifestations of COVID-19 have not yet been comprehensively characterized. Here we used national healthcare databases from the US Department of Veterans Affairs to build a cohort of 153,760 individuals with COVID-19, as well as two sets of control cohorts with 5,637,647 (contemporary controls) and 5,859,411 (historical controls) individuals, to estimate risks and 1-year burdens of a set of pre-specified incident cardiovascular outcomes. We show that, beyond the first 30 d after infection, individuals with COVID-19 are at increased risk of incident cardiovascular disease spanning several categories, including cerebrovascular disorders, dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure and thromboembolic disease. These risks and burdens were evident even among individuals who were not hospitalized during the acute phase of the infection and increased in a graded fashion according to the care setting during the acute phase (non-hospitalized, hospitalized and admitted to intensive care). Our results provide evidence that the risk and 1-year burden of cardiovascular disease in survivors of acute COVID-19 are substantial. Care pathways of those surviving the acute episode of COVID-19 should include attention to cardiovascular health and disease.
Post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)—the virus that causes coronavirus disease 2019 (COVID-19)—can involve the pulmonary and several extrapulmonary organs, including the cardiovascular system1. A few studies have investigated cardiovascular outcomes in the post-acute phase of the COVID-19; however, most were limited to hospitalized individuals (who represent the minority of people with COVID-19), and all had a short duration of follow-up and a narrow selection of cardiovascular outcomes2,3,4,5. A comprehensive assessment of post-acute COVID-19 sequelae of the cardiovascular system at 12 months is not yet available, and studies of post-acute COVID-19 sequelae across the spectrum of care settings of the acute infection (non-hospitalized, hospitalized and admitted to intensive care) are also lacking. Addressing this knowledge gap will inform post-acute COVID-19 care strategies.
In this study, we used the US Department of Veterans Affairs national healthcare databases to build a cohort of 153,760 US veterans who survived the first 30 d of COVID-19 and two control groups: a contemporary cohort consisting of 5,637,647 users of the US Veterans Health Administration (VHA) system with no evidence of SARS-CoV-2 infection and a historical cohort (pre-dating the COVID-19 pandemic) consisting of 5,859,411 non-COVID-19-infected VHA users during 2017. These cohorts were followed longitudinally to estimate the risks and 12-month burdens of pre-specified incident cardiovascular outcomes in the overall cohort and according to care setting of the acute infection (non-hospitalized, hospitalized and admitted to intensive care).
There were 153,760, 5,637,647 and 5,859,411 participants in the COVID-19, contemporary control and historical control groups, respectively (Fig. 1). Median follow-up time in the COVID-19, contemporary control and historical control groups was 347 (interquartile range, 317–440), 348 (318–441) and 347 (317–440) d, respectively. The COVID-19, contemporary control and historical control groups had 159,366, 5,854,288 and 6,082,182 person-years of follow-up, respectively, altogether corresponding to 12,095,836 person-years of follow-up. The demographic and health characteristics of the COVID-19, contemporary control and historical control groups before and after weighting are presented in Supplementary Tables 1 and 2, respectively.
Incident cardiovascular diseases in COVID-19 versus contemporary control
Assessment of covariate balance after application of inverse probability weighting suggested that covariates were well balanced (Extended Data Fig. 1a).
We estimated the risks of a set of pre-specified cardiovascular outcomes in COVID-19 versus contemporary control; we also estimated the adjusted excess burden of cardiovascular outcomes due to COVID-19 per 1,000 persons at 12 months on the basis of the difference between the estimated incidence rate in individuals with COVID-19 and the contemporary control group. Risks and burdens of individual cardiovascular outcomes are provided in Fig. 2 and Supplementary Table 3 and are discussed below. Risks and burdens of the composite endpoints are provided in Fig. 3 and Supplementary Table 3.
People who survived the first 30 d of COVID-19 exhibited increased risk of stroke (hazard ratio (HR) = 1.52 (1.43, 1.62); burden 4.03 (3.32, 4.79) per 10,00 persons at 12 months; for all HRs and burdens, parenthetical ranges refer to 95% confidence intervals (CIs)) and transient ischemic attacks (TIA) (HR = 1.49 (1.37, 1.62); burden 1.84 (1.38, 2.34)). The risks and burdens of a composite of these cerebrovascular outcomes were 1.53 (1.45, 1.61) and 5.48 (4.65, 6.35).
There were increased risks of atrial fibrillation (HR = 1.71 (1.64, 1.79); burden 10.74 (9.61, 11.91)), sinus tachycardia (HR = 1.84 (1.74, 1.95); burden 5.78 (5.07, 6.53)), sinus bradycardia (HR = 1.53 (1.45, 1.62); burden 4.62 (3.90, 5.38)), ventricular arrhythmias (HR = 1.84 (1.72, 1.98); burden 4.18 (3.56, 4.85)); and atrial flutter (HR = 1.80 (1.66, 1.96); burden 3.10 (2.55, 3.69)). The risks and burdens of a composite of these dysrhythmia outcomes were 1.69 (1.64, 1.75), and 19.86 (18.31, 21.46).
Inflammatory disease of the heart or pericardium
Inflammatory disease of the heart or pericardium included pericarditis (HR = 1.85 (1.61, 2.13)); burden 0.98 (0.70, 1.30) and myocarditis (HR = 5.38 (3.80, 7.59); burden 0.31 (0.20, 0.46)). The risks and burdens of a composite of these inflammatory diseases of the heart or pericardium were 2.02 (1.77, 2.30) and 1.23 (0.93, 1.57).
Ischemic heart disease
Ischemic heart disease included acute coronary disease (HR = 1.72 (1.56, 1.90); burden 5.35 (4.13, 6.70)), myocardial infarction (HR = 1.63 (1.51, 1.75); burden 2.91 (2.38, 3.49)), ischemic cardiomyopathy (HR = 1.75 (1.44, 2.13); burden 2.34 (1.37, 3.51)) and angina (HR = 1.52 (1.42, 1.64); burden 2.50 (2.00, 3.03)). The risks and burdens of a composite of these ischemic heart disease outcomes were 1.66 (1.52, 1.80) and 7.28 (5.80, 8.88).
Other cardiovascular disorders
Other cardiovascular disorders included heart failure (HR = 1.72 (1.65, 1.80); burden 11.61 (10.47, 12.78)), non-ischemic cardiomyopathy (HR = 1.62 (1.52, 1.73); burden 3.56 (2.97, 4.20)), cardiac arrest (HR = 2.45 (2.08, 2.89); burden 0.71 (0.53, 0.93)) and cardiogenic shock (HR = 2.43 (1.86, 3.16); burden 0.51 (0.31, 0.77)). The risks and burdens of a composite of these other cardiovascular disorders were 1.72 (1.65, 1.79) and 12.72 (11.54, 13.96).
Thromboembolic disorders included pulmonary embolism (HR = 2.93 (2.73, 3.15); burden 5.47 (4.90, 6.08)); deep vein thrombosis (HR = 2.09 (1.94, 2.24); burden 4.18 (3.62, 4.79)) and superficial vein thrombosis (HR = 1.95 (1.80, 2.12); burden 2.61 (2.20, 3.07)). The risks and burdens of a composite of these thromboembolic disorders were 2.39 (2.27, 2.51) and 9.88 (9.05, 10.74).
Additional composite endpoints
We then examined the risks and burdens of two composite endpoints, including major adverse cardiovascular event (MACE)—a composite of myocardial infarction, stroke and all-cause mortality—and any cardiovascular outcome (defined as the occurrence of any incident pre-specified cardiovascular outcome included in this study). Compared to the contemporary control group, there were increased risks and burdens of MACE (HR = 1.55 (1.50, 1.60); burden 23.48 (21.54, 25.48)) and any cardiovascular outcome (HR = 1.63 (1.59, 1.68); burden 45.29 (42.22, 48.45)).
We examined the risks of incident composite cardiovascular outcomes in subgroups based on age, race, sex, obesity, smoking, hypertension, diabetes, chronic kidney disease, hyperlipidemia and cardiovascular disease. The risks of incident composite cardiovascular outcomes were evident in all subgroups (Fig. 4 and Supplementary Table 4),
We examined the risks and burdens of the pre-specified outcomes in a cohort of people without any cardiovascular disease at baseline; the results were consistent with those shown in the primary analyses (Extended Data Figs. 2 and 3 and Supplementary Table 5).
Incident cardiovascular diseases in COVID-19 versus contemporary control by care setting of the acute infection
We further examined the risks and burdens of cardiovascular diseases in mutually exclusive groups by the care setting of the acute infection (that is, whether people were non-hospitalized (n = 131,612), hospitalized (n = 16,760) or admitted to intensive care (n = 5,388) during the acute phase of COVID-19); demographic and health characteristics of these groups before weighting can be found in Supplementary Table 6 and after weighting in Supplementary Table 7. Assessment of covariate balance after application of weights suggested that covariates were well balanced (Extended Data Fig. 1b). Compared to the contemporary control group, the risks and 12-month burdens of the pre-specified cardiovascular outcomes increased according to the severity of the acute infection (Fig. 5 and Supplementary Table 8); results for the composite outcomes are shown in Fig. 6 and Supplementary Table 8.
Incident cardiovascular diseases in COVID-19 versus historical control
We then examined the associations between COVID-19 and the pre-specified outcomes in analyses considering a historical control group as the referent category; the characteristics of the exposure groups were balanced after weighting (Extended Data Fig. 1c and Supplementary Table 2). The results were consistent with analyses using the contemporary control as the referent category and showed increased risks and associated burdens of the pre-specified outcomes in comparisons of COVID-19 versus the overall historical control group (Extended Data Figs. 4 and 5 and Supplementary Table 9). Using the historical control as the referent category, we examined the risks in subgroups and separately in people without any prior cardiovascular disease; the results were consistent with those undertaken versus the contemporary control (Extended Data Figs. 6–8 and Supplementary Tables 10 and 11). Associations between COVID-19 and our pre-specified outcomes based on care setting of the acute infection were also assessed using the historical control group as the referent category; demographic and clinical characteristics are presented before weighting in Supplementary Table 12 and after weighting in Supplementary Table 13. Characteristics of the exposure groups were balanced after weighting (Extended Data Fig. 1d). The risks and 12-month burdens of the pre-specified outcomes by care setting of the acute infection were also consistent with those shown in analyses considering COVID-19 versus contemporary control (Extended Data Figs. 9 and 10 and Supplementary Table 14).
Cardiovascular diseases before and after COVID-19
To better understand the change in the relative rates of incident cardiovascular outcomes before and after the COVID-19 exposure, we developed a difference-in-differences analysis to estimate the adjusted incident rate ratios of the cardiovascular outcomes relative to both the contemporary and historical control groups in the pre-COVID-19 and post-COVID-19 exposure periods. The results showed that the adjusted incident rate ratios of cardiovascular outcomes in the post-COVID-19 exposure period were significantly higher than those in the pre-exposure period (ratios of incident rate ratios for all cardiovascular outcomes were significantly higher than 1) and exhibited a graded increase by severity of the acute phase of the disease (Supplementary Tables 15–18).
We tested robustness of results in several sensitivity analyses involving the outcomes of MACE and any cardiovascular outcome (Supplementary Tables 17 and 18). The sensitivity analyses were performed in comparisons involving COVID-19 versus the contemporary control and COVID-19 versus the historical control and, additionally, COVID-19 by care setting versus both controls. (1) To test whether the inclusion of additional algorithmically selected covariates would challenge the robustness of study results, we selected and used 300 high-dimensional variables (instead of the 100 used in the primary analyses) to construct the inverse probability weighting. (2) We then also tested the results in models specified to include only pre-defined covariates (that is, without inclusion of algorithmically selected covariates) to build the inverse probability weighting. Finally, (3) we changed the analytic approach by using the doubly robust method (instead of the inverse weighting method used in primary analyses) to estimate the magnitude of the associations between COVID-19 exposure and the pre-specified outcomes. All sensitivity analyses yielded results consistent with those produced using the primary approach (Supplementary Tables 19 and 20).
Risk of myocarditis and pericarditis without COVID-19 vaccination
Because some COVID-19 vaccines might be associated with a very rare risk of myocarditis or pericarditis, and to eliminate any putative contribution of potential vaccine exposure to the outcomes of myocarditis and pericarditis in this study, we conducted two analyses. First, we censored cohort participants at the time of receiving the first dose of any COVID-19 vaccine. Second, we adjusted for vaccination as a time-varying covariate. Both analyses were conducted versus both the contemporary and historical control groups. The results suggested that COVID-19 was associated with increased risk of myocarditis and pericarditis in both analyses (Supplementary Tables 21–24).
Positive and negative outcome controls
To assess whether our data and analytic approach would reproduce known associations, we examined the association between COVID-19 and the risk of fatigue (known to be a signature sequela of post-acute COVID-19) as a positive outcome control. The results suggested that COVID-19 was associated with a higher risk of fatigue (Supplementary Table 25).
We then examined the association between COVID-19 and a battery of seven negative-outcome controls where no prior knowledge suggests that an association is expected. The results yielded no significant association between COVID-19 and any of the negative-outcome controls, which were consistent with a priori expectations (Supplementary Table 25).
To further examine the robustness of our approach, we developed and tested a pair of negative-exposure controls. We hypothesized that receipt of influenza vaccination in odd-numbered and even-numbered calendar days between 1 March 2020 and 15 January 2021 would be associated with similar risks of the pre-specified cardiovascular outcomes examined in this analysis. We, therefore, tested the associations between receipt of influenza vaccine in even-numbered (n = 571,291) versus odd-numbered (n = 605,453) calendar days and the pre-specified cardiovascular outcomes. We used the same data sources, cohort design, analytical approach (including covariate specification and weighting method) and outcomes. The results suggest that receipt of influenza vaccination in odd-numbered calendar days versus even-numbered calendar days was not significantly associated with any of the pre-specified cardiovascular outcomes (Supplementary Table 26).
In this study involving 153,760 people with COVID-19, 5,637,647 contemporary controls and 5,859,411 historical controls—which, altogether, correspond to 12,095,836 person-years of follow-up—we provide evidence that, beyond the first 30 d of infection, people with COVID-19 exhibited increased risks and 12-month burdens of incident cardiovascular diseases, including cerebrovascular disorders, dysrhythmias, inflammatory heart disease, ischemic heart disease, heart failure, thromboembolic disease and other cardiac disorders. The risks were evident regardless of age, race, sex and other cardiovascular risk factors, including obesity, hypertension, diabetes, chronic kidney disease and hyperlipidemia; they were also evident in people without any cardiovascular disease before exposure to COVID-19, providing evidence that these risks might manifest even in people at low risk of cardiovascular disease. Our analyses of the risks and burdens of cardiovascular outcomes across care settings of the acute infection reveal two key findings: (1) that the risks and associated burdens were evident among those who were not hospitalized during the acute phase of the disease—this group represents the majority of people with COVID-19; and (2) that the risks and associated burdens exhibited a graded increase across the severity spectrum of the acute phase of COVID-19 (from non-hospitalized to hospitalized individuals to those admitted to intensive care). The risks and associated burdens were consistent in analyses considering the contemporary control group and, separately, the historical control group as the referent category. The difference-in-differences analyses, which are designed to further investigate the causality of study findings, show that the increased risks of post-acute COVID-19 cardiovascular outcomes are attributable sequelae to COVID-19 itself. The results were robust to challenge in multiple sensitivity analyses. Application of a positive-outcome control yielded results consistent with established knowledge; and testing of a battery of negative-outcome controls and negative-exposure controls yielded results consistent with a priori expectations. Taken together, our results show that 1-year risks and burdens of cardiovascular diseases among those who survive the acute phase of COVID-19 are substantial and span several cardiovascular disorders. Care strategies of people who survived the acute episode of COVID-19 should include attention to cardiovascular health and disease.
The broader implications of these findings are clear. Cardiovascular complications have been described in the acute phase of COVID-19 (refs. 6,7,8). Our study shows that the risk of incident cardiovascular disease extends well beyond the acute phase of COVID-19. First, the findings emphasize the need for continued optimization of strategies for primary prevention of SARS-CoV-2 infections; that is, the best way to prevent Long COVID and its myriad complications, including the risk of serious cardiovascular sequelae, is to prevent SARS-CoV-2 infection in the first place. Second, given the large and growing number of people with COVID-19 (more than 72 million people in the United States, more than 16 million people in the United Kingdom and more than 355 million people globally), the risks and 12-month burdens of cardiovascular diseases reported here might translate into a large number of potentially affected people around the world. Governments and health systems around the world should be prepared to deal with the likely significant contribution of the COVID-19 pandemic to a rise in the burden of cardiovascular diseases. Because of the chronic nature of these conditions, they will likely have long-lasting consequences for patients and health systems and also have broad implications on economic productivity and life expectancy. Addressing the challenges posed by Long COVID will require a much-needed, but so far lacking, urgent and coordinated long-term global response strategy9,10.
The mechanism or mechanisms that underlie the association between COVID-19 and development of cardiovascular diseases in the post-acute phase of the disease are not entirely clear11,12. Putative mechanisms include lingering damage from direct viral invasion of cardiomyocytes and subsequent cell death, endothelial cell infection and endotheliitis, transcriptional alteration of multiple cell types in heart tissue, complement activation and complement-mediated coagulopathy and microangiopathy, downregulation of ACE2 and dysregulation of the renin–angiotensin–aldosterone system, autonomic dysfunction, elevated levels of pro-inflammatory cytokines and activation of TGF-β signaling through the Smad pathway to induce subsequent fibrosis and scarring of cardiac tissue11,13,14,15,16,17. An aberrant persistent hyperactivated immune response, autoimmunity or persistence of the virus in immune-privileged sites has also been cited as putative explanations of extrapulmonary (including cardiovascular) post-acute sequelae of COVID-19 (refs. 11,13,14,18). Integration of the SARS-CoV-2 genome into DNA of infected human cells, which might then be expressed as chimeric transcripts fusing viral with cellular sequences, has also been hypothesized as a putative mechanism for continued activation of the immune-inflammatory-procoagulant cascade19,20. These mechanistic pathways might explain the range of post-acute COVID-19 cardiovascular sequelae investigated in this report. A deeper understanding of the biologic mechanisms will be needed to inform development of prevention and treatment strategies of the cardiovascular manifestations among people with COVID-19.
Our analyses censoring participants at time of vaccination and controlling for vaccination as a time-varying covariate show that the increased risk of myocarditis and pericarditis reported in this study is significant in people who were not vaccinated and is evident regardless of vaccination status.
This study has several strengths. We used the vast and rich national healthcare databases of the US Department of Veterans Affairs to build a large cohort of people with COVID-19. We designed the study cohort to investigate incident cardiovascular disease in the post-acute phase of the disease. We pre-specified a comprehensive list of cardiovascular outcomes. We examined the associations using two large control groups: a contemporary and a historical control; this approach allowed us to deduce that the associations between COVID-19 and risks of cardiovascular outcomes are not related to the broader temporal changes between the pre-pandemic and the pandemic eras but, rather, are related to exposure to COVID-19 itself. Our modeling approach included specification of 19 pre-defined variables selected based on established knowledge and 100 algorithmically selected variables from high-dimensional data domains, including diagnostic codes, prescription records and laboratory test results. We evaluated the associations across care settings of the acute infection. Our difference-in-differences approach further enhances the causal interpretation of study results. We challenged the robustness of results in multiple sensitivity analyses and successfully tested positive-outcome and negative-outcome controls and negative-exposure controls. We provided estimates of risk on both the ratio scale (HRs) and the absolute scale (burden per 1,000 persons at 12 months); the latter also reflects the contribution of baseline risk and provides an estimate of potential harm that is more easily explainable to the public than risk reported on the ratio scale (for example, HR).
This study has several limitations. The demographic composition of our cohort (majority White and male) might limit the generalizability of study findings. We used the electronic healthcare databases of the US Department of Veterans Affairs to conduct this study, and, although we used validated outcome definitions and took care to adjust the analyses for a large set of pre-defined and algorithmically selected variables, we cannot completely rule out misclassification bias and residual confounding. It is possible that some people might have had COVID-19 but were not tested for it; these people would have been enrolled in the control group and, if present in large numbers, might have biased the results toward the null. Our datasets do not include information on causes of death. Finally, as the pandemic, with all its dynamic features, continues to progress, as the virus continues to mutate and as new variants emerge, as treatment strategies of acute and post-acute COVID-19 evolve and as vaccine uptake improves, it is possible that the epidemiology of cardiovascular manifestations in COVID-19 might also change over time21.
In summary, using a national cohort of people with COVID-19, we show that risk and 12-month burden of incident cardiovascular disease are substantial and span several cardiovascular disease categories (ischemic and non-ischemic heart disease, dysrhythmias and others). The risks and burdens of cardiovascular disease were evident even among those whose acute COVID-19 did not necessitate hospitalization. Care pathways of people who survived the acute episode of COVID-19 should include attention to cardiovascular health and disease.
We used the electronic healthcare databases of the US Department of Veterans Affairs to conduct this study. The VHA, within the US Department of Veterans Affairs, provides healthcare to discharged veterans of the US armed forces. It operates the largest nationally integrated healthcare system in the United States, with 1,255 healthcare facilities (including 170 VA Medical Centers and 1,074 outpatient sites) located across the United States. All veterans who are enrolled with the VHA have access to the comprehensive medical benefits package of the VA (which includes preventative and health maintenance, outpatient care, inpatient hospital care, prescriptions, mental healthcare, home healthcare, primary care, specialty care, geriatric and extended care, medical equipment and prosthetics). The VA electronic healthcare databases are updated daily.
A flowchart of cohort construction is provided in Fig. 1. Of 6,241,346 participants who encountered the VHA in 2019, 162,690 participants who had a positive COVID-19 test between 1 March 2020 and 15 January 2021 were selected into the COVID-19 group. To examine post-acute outcomes, we then selected participants from the COVID-19 group who were alive 30 d after the date of the positive COVID-19 test (n = 153,760). The date of the COVID-19-positive test served as T0 for the COVID-19 group.
A contemporary control group of people with no evidence of SARS-CoV-2 infection was constructed from those who had encountered the VHA in 2019 (n = 6,241,346). Of those who were still alive by 1 March 2020 (n = 5,960,737), 5,806,977 participants were not in the COVID-19 group and were selected into the contemporary control group. To ensure that this contemporary control group had a similar follow-up time as the COVID-19 group, we randomly assigned T0 in the contemporary control group based on the distribution of T0 in the COVID-19 group so that the proportion of people enrolled on a certain date would be the same in both the contemporary and COVID-19 groups. Of 5,658,938 participants alive at the assigned T0, 5,637,647 participants in the contemporary control group were alive 30 d after T0. In the COVID-19 and contemporary control groups, 31 October 2021 was the end of follow-up.
To examine the associations between COVID-19 and cardiovascular outcomes compared to those who did not experience the pandemic, a historical control group was constructed from 6,461,205 participants who used the VHA in 2017. Of the 6,150,594 participants who were alive on 1 March 2018, 6,008,499 participants did not enroll into the COVID-19 group and were further selected into the historical control group. To ensure that this historical control group had a similar follow-up time as the COVID-19 group, we randomly assigned T0 in the historical control group with a similar distribution as T0 minus 2 years (730 d) in the COVID-19 group. Of 5,875,818 historical control participants alive at assigned T0, 5,859,411 were alive 30 d after T0. In the historical control group, end of follow-up was set as 31 October 2019.
Electronic health records from the VA Corporate Data Warehouse (CDW) were used in this study. Demographic information was collected from the CDW Patient domain. The CDW Outpatient Encounters domain provided clinical information pertaining to outpatient encounters, whereas the CDW Inpatient Encounters domain provided clinical information during hospitalization. Medication information was obtained from the CDW Outpatient Pharmacy and CDW Bar Code Medication Administration domains. The CDW Laboratory Results domain provided laboratory test information, and the COVID-19 Shared Data Resource provided information on COVID-19. Additionally, the Area Deprivation index (ADI), which is a composite measure of income, education, employment and housing, was used as a summary measure of contextual disadvantage at participants’ residential locations22.
The pre-specified outcomes were selected based on our previous work on the systematic characterization of Long COVID1,23. Incident cardiovascular outcomes in the post-acute phase of COVID-19 were assessed in the follow-up period between 30 d after T0 until the end of follow-up in those without history of the outcome in the year before T0. Each cardiovascular outcome was defined based on validated diagnostic codes. We also aggregated individual outcomes in a related category of composite outcome (for example, stroke and TIA were aggregated to cerebrovascular disease). We also specified two additional composite outcomes: (1) MACE was a composite outcome of all-cause mortality, myocardial infarction and stroke; and (2) the composite of any cardiovascular outcome was defined as the first incident occurrence of any of the cardiovascular outcomes investigated in this study.
To adjust for the difference in baseline characteristics between groups, we considered both pre-defined and algorithmically selected high-dimensional covariates assessed within 1 year before T0. Pre-defined variables were selected based on prior knowledge1,7,24,25. The pre-defined covariates included age, race (White, Black and Other), sex, ADI, body mass index, smoking status (current, former and never) and healthcare use parameters, including the use number of outpatient and inpatient encounters and use of long-term care. We additionally specified several comorbidities as pre-defined variables, including cancer, chronic kidney disease, chronic lung disease, dementia, diabetes, dysautonomia, hyperlipidemia and hypertension. Additionally, we adjusted for estimated glomerular filtration rate and systolic and diastolic blood pressure. Missing values were accounted for by conditional mean imputation based on value within the group26. Continuous variables were transformed into restricted cubic spline functions to account for potential non-linear relationships.
In addition to pre-defined covariates, we further algorithmically selected additional potential confounders from data domains, including diagnoses, medications and laboratory tests27. To accomplish this, we gathered all patient encounter, prescription and laboratory data and classified the information into 540 diagnostic categories, 543 medication classes and 62 laboratory test abnormalities. For the diagnoses, medications and laboratory abnormalities that occurred in at least 100 participants within each group, univariate relative risk between the variable and exposure was calculated, and the top 100 variables with the strongest relative risk were selected28. The process of algorithmically selecting the high-dimensional covariates was independently conducted for each outcome-specific cohort in each comparison (for example, the COVID-19 versus contemporary control analyses to examine incident heart failure and the COVID-19 versus historical control analyses to examine incident heart failure).
All pre-defined and algorithmically selected covariates were used in the models.
Baseline characteristics of the COVID-19 and contemporary and historical control groups, along with standardized mean difference between groups, were described.
We then estimated the risks, burdens and excess burdens of incident cardiovascular outcomes for COVID-19 compared to the contemporary control group and, separately, compared to the historical control group, after adjusting for differences in baseline characteristics through inverse probability weighting. To estimate the risk of each incident cardiovascular outcome, we built a subcohort of participants without a history of the outcome being examined (that is, the risk of incident heart failure was estimated within a subcohort of participants without history of heart failure in the year before enrollment). In each subcohort, a propensity score for each individual was estimated as the probability of belonging to the VHA users group in 2019 (target population) based on both pre-defined and algorithmically selected high-dimensional variables. This propensity score was then used to calculate the inverse probability weight as the probability of belonging in the target population divided by 1 − the probability of being in the target population. Covariate balance after application of weights was assessed by standardized mean differences.
HRs of incident cardiovascular outcomes between the COVID-19 and contemporary cohorts and the COVID-19 and historical cohorts were estimated from cause-specific hazard models where death was considered as a competing risk, and the inverse probability weights were applied. Burden per 1,000 participants at 12 months of follow-up and the excess burden based on the differences between COVID-19 and control groups were estimated.
We conducted analyses in subgroups by age, race, sex, obesity, smoking, hypertension, diabetes, chronic kidney disease, hyperlipidemia and cardiovascular disease. And, separately, we undertook analyses in a cohort without history of any cardiovascular outcomes before cohort enrollment.
We then developed causal difference-in-differences analyses to estimate the adjusted incident rate ratios of all cardiovascular outcomes in the pre-COVID-19 and post-COVID-19 exposure period relative to both contemporary and historical controls29,30,31,32. To enhance the interpretability of difference-in-difference analyses, the pre-exposure period was defined as with same follow-up time as the post-exposure period, and the incident rate ratio for the pre-exposure period was examined within those without history of the outcome within 1 year before the period. Incident rate ratios for all groups in the pre-exposure and post- exposure periods were weighted toward the common target population (VHA users in 2019) based on pre-exposure characteristics. The adjusted incident rate ratios in the pre-exposure and post-exposure periods were then compared. Difference-in-differences analyses were also conducted in mutually exclusive groups according to care setting of the acute phase of the disease. We also evaluated the associations between COVID-19 and risks of post-acute cardiovascular sequelae in mutually exclusive groups according to care setting of the acute phase of the disease (that is, whether people were non-hospitalized, hospitalized or admitted into the intensive care unit during the first 30 d of infection). Inverse probability weights were estimated for each care setting group using the approach outlined in the previous paragraph. Cause-specific hazard models with inverse probability weighting were then applied, and HRs, burdens and excess burdens were reported.
We conducted multiple sensitivity analyses to test the robustness of our study results. (1) To capture additional potential confounders, we expanded our inclusion of high-dimensional variables from the top 100 to the top 300 when constructing the inverse probability weight. (2) We then modified our adjustment strategy by using only pre-defined variables when constructing the inverse probability weight (not including the 100 high-dimensional covariates used in the primary analyses). Finally, (3) we alternatively applied a doubly robust approach, where both covariates and the inverse probability weights were applied to the survival models, to estimate the associations33.
COVID-19 is associated with an increased risk of fatigue in the post-acute phase of the disease, which is generally considered as a signature post-acute sequela34. To test whether our approach would reproduce known associations, we, therefore, examined the association between COVID-19 and fatigue as a positive outcome control. Reproducing this known association (using our data, cohort design and analytic strategy) would provide some measure of assurance that our approach yields result consistent with a priori expectations.
We also subjected our approach to the application of a battery of negative-outcome controls where no prior knowledge supports the existence of a causal association between the exposure and the risks of negative-outcome controls35. The negative-outcome controls included hypertrichosis, melanoma in situ, sickle cell trait, perforation of the tympanic membrane, malignant neoplasm of the tongue, B cell lymphoma and Hodgkin’s lymphoma. We also developed and tested a pair of negative-exposure controls (defined as exposure to influenza vaccine in odd-numbered or even-numbered calendar days between 1 March 2020 and 15 January 2021). Our pre-test expectation was that there would be no differences in risk of any of the pre-specified cardiovascular outcomes examined in this analysis between those who received influenza vaccine in odd-numbered versus even-numbered calendar days. The successful application of negative controls might reduce concern about the presence of spurious biases related to cohort building, study design, covariate selection, analytic approaches, outcome ascertainment, residual confounding and other sources of latent biases.
Estimation of variance when weightings were applied was accomplished by using robust sandwich variance estimators. In all analyses, a 95% confidence interval that excluded unity was considered evidence of statistical significance. This study was approved by the institutional review board of the VA St. Louis Health Care System (protocol number 1606333), which granted a waiver of informed consent. Analyses were conducted using SAS Enterprise Guide version 8.2 (SAS Institute), and results were visualized using R version 4.04.
This research project was reviewed and approved by the institutional review board of the VA St. Louis Health Care System (protocol number 1606333).
The data that support the findings of this study are available from the US Department of Veterans Affairs. VA data are made freely available to researchers behind the VA firewall with an approved VA study protocol. For more information, visit https://www.virec.research.va.gov or contact the VA Information Resource Center at VIReC@va.gov.
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This study used data from the VA COVID-19 Shared Data Resource. This research was funded by the US Department of Veterans Affairs (to Z.A.-A.) and two American Society of Nephrology and KidneyCure fellowship awards (to Y.X. and B.B.). The contents do not represent the views of the US Department of Veterans Affairs or the US government.
Peer Reviewed Medical Papers Submitted To Various Medical Journals, Evidencing A Multitude Of Adverse Events In Covid-19 Vaccine Recipients.
The list includes studies published as of January 20, 2022 concerning the potential adverse reaction from COVID-19 vaccines, such as myocarditis, thrombosis, thrombocytopenia, vasculitis, cardiac, Bell’s Palsy, immune-mediated disease, and many more.
Occurrence of acute infarct-like myocarditis after COVID-19 vaccination: just an accidental coincidence or rather a vaccination-associated autoimmune myocarditis?: https://pubmed.ncbi.nlm.nih.gov/34333695/
This list is not meant to be all inclusive of all peer-reviewed potential harms from mRNA vaccines. To access any of the 1,000 Vaccine Harms published in Medical journals Click The Link Below: