Real-world Effectiveness of BNT162b2 in Children and Adolescents in Preventing Infection and Severe Diseases with SARS-CoV-2 During the Delta and Omicron Periods: Findings from Trial Emulation Using an EHR-based Cohort (preprint)

BACKGROUND The current understanding of the long-term effectiveness of the BNT162b2 vaccine for a range of outcomes across diverse U.S. pediatric populations is limited. In this study, we assessed the effectiveness of BNT162b2 against various strains of the SARS-CoV-2 virus using data from a national collaboration of pediatric health systems (PEDSnet). METHODS We emulated three target trials to assess the real-world effectiveness of BNT162b2: adolescents aged 12 to 20 years during the Delta variant period (Target trial 1), children aged 5 to 11 years (Target trial 2) and adolescents aged 12 to 20 years during the Omicron variant period (Target trial 3). The outcomes included documented infection, COVID-19 illness severity, admission to an intensive care unit (ICU), and two cardiac-related outcomes, myocarditis and pericarditis. In the U.S., immunization records are often captured and stored across multiple disconnected sources, resulting in incomplete vaccination records in patients' electronic health records (EHR). We implemented a novel trial emulation pipeline accounting for possible misclassification bias in vaccine documentation in EHRs. The effectiveness of the BNT162b2 vaccine was estimated from the Poisson regression model with confounders balanced via propensity score stratification. RESULTS During the Delta period, the BNT162b2 vaccine demonstrated an overall effectiveness 98.4% (95% CI, 98.1 to 98.7) against documented infection among adolescents, with no significant waning after receipt of the first dose. During the Omicron period, the overall effectiveness was estimated to be 74.3% (95% CI, 72.2 to 76.2) in preventing documented infection among children, which was higher against moderate or severe COVID-19 (75.5%; 95% CI, 69.0 to 81.0) and ICU admission with COVID-19 (84.9%; 95% CI, 64.8 to 93.5). In the adolescent population, the overall effectiveness against documented Omicron infection was 85.5% (95% CI, 83.8 to 87.1), with effectiveness of 84.8% (95% CI, 77.3 to 89.9) against moderate or severe COVID-19, and 91.5% (95% CI, 69.5 to 97.6) against ICU admission with COVID-19. The effectiveness of the BNT162b2 vaccine against the Omicron variant declined after 4 months following the first dose and then stabilized with higher levels of uncertainty. Across all three cohorts, the risk of cardiac outcomes was approximately 65% to 85% lower in the vaccinated group than that of the unvaccinated group accounting for possible misclassification bias. CONCLUSIONS This study suggests BNT162b2 was effective among children and adolescents in Delta and Omicron periods for a range of COVID-19-related outcomes and is associated with a lower risk for cardiac complications. Waning effectiveness over time suggests that revaccination may be needed in the future.

Alteration in follow-up echocardiographic indices in patients with COVID-19: a prospective cohort study (preprint)

Background Cardiac problems are frequent (20 to 25%) with COVID-19 and are associated with cardiac complications and in-hospital mortality. Existing research on the echocardiographic examination of COVID-19 focuses mostly on hospitalized patients with severe symptoms and in the acute phase of the disease, leaving out of the spotlight non-hospitalized individuals with mild symptoms. In this study, we wanted to determine the long-term influence of both severe and non-severe COVID-19 on echocardiographic changes. Methods This prospective cohort study was conducted during Iran's third COVID-19 wave in November 2020 among healthcare workers with a history of COVID-19 but otherwise healthy. Initially, a total of 100 patients underwent the primary echocardiographic examination 6 to 8 weeks following COVID-19 onset, and 6 months after the COVID-19 diagnosis, 64 subjects underwent the secondary echocardiographic evaluations. Based on clinical or radiological evidence, individuals were categorized into two groups of non-severe and severe COVID-19. Results Of 64 participants, 42 (65.6%) were women. The patients ' mean age was 40.4±8.1 years. In the non-severe COVID-19 group, among left ventricular (LV) echocardiographic indices, stroke volume index and ejection fraction increased significantly (24.7±4.1 cc/m2 vs. 29.7±7.0 cc/m2, p-value<0.001 and 61.9% [59.8-64.5] vs. 63.8% [58.2-68.9], p-value=0.029, respectively). Among right ventricular indices, free-wall global longitudinal strain decreased significantly in the secondary echocardiogram: (-32.3±4.6% vs. -28.8±5.8%, p-value=0.002). In the severe COVID-19 group, from LV echocardiographic indices, global longitudinal strain increased significantly over the follow-up period (-20% [-21.4- -19] vs. -23.9% [-25.3--21.9], p-value=0.004) and from RV indices, the fractional area change showed a significant decrease (47.2% [42.3-52.2] vs. 36.4% [31.1-45], p-value=0.002). Conclusion Although some patterns of significant change were seen among echocardiographic indices, COVID-19, regardless of severity, did not lead to cardiac impairment in an otherwise healthy population. The current results may not present the outcomes of older adults or with a history of cardiac problems against COVID-19.

Cryptogenic Stroke In The Context of Pandemic-Related Stress: The Role of Arterial Hemodynamics.

BACKGROUND: Up to 45% of ischemic strokes are cryptogenic, which is an impediment to proposing preventative measures. In this investigation we aimed to study underlying heart arrhythmias in patients with cryptogenic stroke, taking into consideration the context of the COVID-19 pandemic and stressful lockdown conditions. SUBJECTS AND METHODS: In this cross-sectional study we observed 52 patients with cryptogenic stroke >1 month after acute presentation, and a control group consisting of 88 patients without stroke. All patients undewent the laboratory and instrumental investigation consisting of the following: lipid spectrum; hemostasiograms; hemoglobin A1c; transthoracic or/and transesophageal echocardiography; 24-hours monitoring of ECG; computer tomography or magnetic resonance imaging of the brain. We studied the hemodynamics of the common carotid arteries using Doppler ultrasound imaging and digital sphygmography (SG). RESULTS: The groups were indentical with respect to the preponderance of study parameters (sex, age, comorbidities, instrumental and laboratory data). The ischemic stroke group had a statistically significant difference in the prevalence of the first type of extrasystolic arrhythmia according to our gradation of extrasystoles, which are ventricular systoles of extrasystolic contraction appearing before the transmitral blood flow peak (peak E in echocardiography). We observed that earlier ventricular systoles of extrasystole in the cardiac cycle predicted for greater growth of hemodynamic and kinetic parameters. Calculating the indices of a four-field table established the significant relationship between the moment of appearance of extrasystolic ventricular contraction in the cardiac cycle and the risk for cryptogenic stroke (normalized value of the Pearson coefficient (C`) of the two paramaters was 0.318). CONCLUSIONS: Extrasystolic arrhythmia appeared as an additional risk factor of earlier stroke. The most dangerous type of arrhythmia was when the ventricular contraction of the extrasystole appeared before the transmitral blood flow peak in the cardiac cycle. This observation could present a risk-marker for brain-related cardiovascular complications such as stroke, which might be patients suffering from different internal diseases, especially in the context of environmental stress conditions of the current pandemic and its related lockdown measures.

Parallel use of pluripotent human stem cell lung and heart models provide new insights for treatment of SARS-CoV-2 (preprint)

SARS-CoV-2 primarily infects the respiratory tract, but pulmonary and cardiac complications occur in severe COVID-19. To elucidate molecular mechanisms in the lung and heart, we conducted paired experiments in human stem cell-derived lung alveolar type II (AT2) epithelial cell and cardiac cultures infected with SARS-CoV-2. With CRISPR-Cas9 mediated knock-out of ACE2, we demonstrated that angiotensin converting enzyme 2 (ACE2) was essential for SARS-CoV-2 infection of both cell types but further processing in lung cells required TMPRSS2 while cardiac cells required the endosomal pathway. Host responses were significantly different; transcriptome profiling and phosphoproteomics responses depended strongly on the cell type. We identified several antiviral compounds with distinct antiviral and toxicity profiles in lung AT2 and cardiac cells, highlighting the importance of using several relevant cell types for evaluation of antiviral drugs. Our data provide new insights into rational drug combinations for effective treatment of a virus that affects multiple organ systems.

Occurrence of relative bradycardia and relative tachycardia in individuals diagnosed with COVID-19 (preprint)

Background: The COVID-19 disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS- CoV-2) has become one of the worst global pandemics of the century causing tremendous human and economic suffering worldwide. While considered a respiratory disease, COVID-19 is known to cause cardiac complications. Wearable devices are well equipped to measure heart rate continuously and their popularity makes them valuable devices in the field of digital health. In this article, we use Fitbit devices to examine resting heart rate from individuals diagnosed with COVID-19. Methods: The Fitbit COVID-19 survey was conducted from May 2020 - June 2021. We collected resting heart rate data from 7,200 individuals (6,606 symptomatic, 594 asymptomatic) diagnosed with COVID- 19 between March 2020 - December 2020, as well as from 463 individuals diagnosed with influenza between January 2020 - December 2020. Data from healthy individuals served as a control, in order to model the seasonal variation. We also computed heart rate variability and respiratory rate data for symptomatic COVID-19. Findings: Resting Heart Rate is elevated during COVID-19 symptom onset, with average peak increases relative to the baseline of 1.8%+/-0.1% (3.4%+/-0.2%) for females (males), where the quoted numbers are mean and standard error of the mean. After the initial peak, the resting heart rate decreased and reached a minimum on average ~ 13 days after symptom onset. The minimum value relative to the baseline is more negative for females (-1.75% +/- 0.1%) compared to males (0.08% +/- 0.2%). The resting heart rate then increased, reaching a second peak on average ~ 28 days from symptom onset, before falling back to the baseline ~ 112 days from symptom onset. All estimates vary with disease severity. Interpretation: The resting heart rate is modified for several months following a COVID-19 diagnosis. Interestingly, this effect is seen with seasonal influenza also, although the bradycardia minimum and the second tachycardia peak are often more pronounced in the case of symptomatic COVID-19. By computing resting heart rate daily, wearable devices can contribute to monitoring wellness during recovery from COVID-19, and seasonal influenza. Funding: A.N., H.-W.S., and C.H. are supported by Fitbit Research, Google LLC.

Cardiac complications and pertaining mortality rate in COVID-19 patients; a systematic review and meta-analysis (preprint)

Background Raising knowledge over cardiac complications and managing them can play a key role in their recovery. In this study, we aim to investigate the evidence regarding the prevalence of cardiac complications and the resulting mortality rate in COVID-19 patients.Results The initial search resulted in 853 records, from which 40 articles were included. Overall analysis showed the prevalence of acute cardiac injury, heart failure and cardiac arrest were 19.46% (95% CI: 18.23–20.72), 19.07% (95% CI: 15.38–23.04) and 3.44% (95% CI: 3.08–3.82), respectively. Moreover, abnormal serum troponin level was observed in 22.86% (95% CI: 21.19–24.56) of the COVID-19 patients. Further analysis revealed that the overall odds of mortality is 14.24 [odds ratio (OR) = 14.24; 95% CI: 8.67–23.38] times higher, when patients develop acute cardiac injury. The pooled odds ratio of mortality when the analysis was limited to abnormal serum troponin level was 19.03 (OR = 19.03; 95% CI: 11.85–30.56).Conclusion Acute cardiac injury and abnormal serum troponin level were the most prevalent cardiac complications/abnormalities in COVID-19 patients. The importance of cardiac complications becomes crucial due to the higher mortality rate among patients with these complications. Thus, troponin screenings and cardiac evaluations are recommended to be performed in routine patient assessments.

Systematic Review and Meta-analysis of the Safety of Chloroquine and Hydroxychloroquine From Randomized Controlled Trials on Malarial and Non-malarial Conditions (preprint)

Background: Despite the expectations regarding the effectiveness of chloroquine (CQ) and hydroxychloroquine (HCQ) for coronavirus disease (COVID-19) management, concerns about their adverse events have remained. Objectives: The objective of this systematic review was to evaluate the safety of CQ and HCQ from malarial and non-malarial randomized clinical trials (RCTs). Methods: The primary outcomes were the frequencies of serious adverse events (SAEs), retinopathy, and cardiac complications. Search strategies were applied to MEDLINE, EMBASE, LILACS, CENTRAL, Scopus, and Trip databases. We used random-effects model to pool results across studies and Peto one-step odds ratio (OR) for event rates below 1 %. Both-armed zero-event studies were excluded from the meta-analyses. We used the Grading of Recommendations Assessment, Development, and Evaluation system to evaluate the certainty of evidence.Results: Ninety-two RCTs were included. We found no significant difference between CQ/HCQ and control (placebo or non-CQ/HCQ) in the frequency of SAEs (OR: 0.98, 95 % confidence interval [CI]: 0.71–1.36, 25 trials, 11,605 participants, moderate certainty of evidence). No clear relationship was observed between CQ/HCQ and retinopathy (OR: 1,63, 95 % CI: -0.4–6.57, 5 trials, 344 participants, very low certainty of evidence). There was a low certainty of evidence of the effect of CQ/HCQ versus control on cardiac complications (Relative risk: 1.48, 95 % CI: 1.1–1.98, 8 trials, 5,970 participants).Conclusions: CQ and HCQ might be safe, with low frequency of SAEs on malarial and non-malarial conditions. No clear effect of their use on the incidence of retinopathy and cardiac complications was observed.The protocol for this systematic review was registered with PROSPERO (registration number: CRD42020177818)

First Case of COVID-19 Complicated with Fulminant Myocarditis: A case Report and Insights (preprint)

Background: Coronavirus Disease 2019 (COVID-19) has been demonstrated to be the cause of pneumonia. Nevertheless, it has not been reported as the cause of acute myocarditis or fulminant myocarditis. Case presentation: A 63-year-old male was admitted with pneumonia and cardiac symptoms. He was genetically confirmed as having COVID-19 according to sputum testing on the day of admission. He also had elevated troponin I (Trop I) level (up to 11.37 g/L) and diffuse myocardial dyskinesia along with a decreased left ventricular ejection fraction (LVEF) on echocardiography. The highest level of interleukin-6 was 272.40 pg/ml. Bedside chest radiographs showed typical ground-glass changes indicative of viral pneumonia. Laboratory test results for viruses that cause myocarditis were all negative. The patient conformed to the diagnostic criteria of the Chinese expert consensus statement for fulminant myocarditis. After receiving antiviral therapy and mechanical life support, Trop I was reduced to 0.10 g/L, and interleukin-6 was reduced to 7.63 pg/ml. Moreover, the LVEF of the patient gradually recovered to 68%. The patient died of aggravation of secondary infection on the 33rd day of hospitalization. Conclusion: COVID-19 patients may develop severe cardiac complications such as myocarditis and heart failure. This is the first report of COVID-19 complicated with fulminant myocarditis. The mechanism of cardiac pathology caused by COVID-19 needs further study.

Acute Myocardial Injury of Patients with Coronavirus Disease 2019 (preprint)

Background: Since the outbreak of the Coronavirus Disease 2019 (COVID-19) in China, respiratory manifestations of the disease have been observed. However, as a fatal comorbidity, acute myocardial injury (AMI) in COVID-19 patients has not been previously investigated in detail. We investigated the clinical characteristics of COVID-19 patients with AMI and determined the risk factors for AMI in them. Methods: We analyzed data from 53 consecutive laboratory-confirmed and hospitalized COVID-19 patients (28 men, 25 women; age, 19-81 years). We collected information on epidemiological and demographic characteristics, clinical features, routine laboratory tests (including cardiac injury biomarkers), echocardiography, electrocardiography, imaging findings, management methods, and clinical outcomes. Results: Cardiac complications were found in 42 of the 53 (79.25%) patients: tachycardia (n=15), electrocardiography abnormities (n=11), diastolic dysfunction (n=20), elevated myocardial enzymes (n=30), and AMI (n=6). All the six AMI patients were aged >60 years; five of them had two or more underlying comorbidities (hypertension, diabetes, cardiovascular diseases, and chronic obstructive pulmonary disease). Novel coronavirus pneumonia (NCP) severity was higher in the AMI patients than in patients with non-definite AMI (p<0.001). All the AMI patients required care in intensive care unit; of them, three died, two remain hospitalized. Multivariate analyses showed that C-reactive protein (CRP) levels, NCP severity, and underlying comorbidities were the risk factors for cardiac abnormalities in COVID-19 patients. Conclusions: Cardiac complications are common in COVID-19 patients. Elevated CRP levels, underlying comorbidities, and NCP severity are the main risk factors for cardiac complications in COVID-19 patients.