Meeting the Challenges of Myocarditis: New Opportunities for Prevention, Detection, and Intervention-A Report from the 2021 National Heart, Lung, and Blood Institute Workshop.

The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of international experts to discuss new research opportunities for the prevention, detection, and intervention of myocarditis in May 2021. These experts reviewed the current state of science and identified key gaps and opportunities in basic, diagnostic, translational, and therapeutic frontiers to guide future research in myocarditis. In addition to addressing community-acquired myocarditis, the workshop also focused on emerging causes of myocarditis including immune checkpoint inhibitors and SARS-CoV-2 related myocardial injuries and considered the use of systems biology and artificial intelligence methodologies to define workflows to identify novel mechanisms of disease and new therapeutic targets. A new priority is the investigation of the relationship between social determinants of health (SDoH), including race and economic status, and inflammatory response and outcomes in myocarditis. The result is a proposal for the reclassification of myocarditis that integrates the latest knowledge of immunological pathogenesis to refine estimates of prognosis and target pathway-specific treatments.

Epidemiology of COVID-19 and Its Cardiac and Neurologic Complications Among Chinese and South Asians in Ontario: Waves 1, 2, and 3.

Background: Although we had previously reported the cardiac and neurologic outcomes of Chinese and South Asian Ontarians in wave 1 of COVID-19, data on subsequent waves of COVID-19 remain unexamined. This is an extension study of this cohort in waves 2 and 3. Methods: We identified adult Ontarians with a positive COVID-19 polymerase chain reaction test from January 1, 2020 to June 30, 2021, and they were classified as being Chinese or South Asian using a validated surname algorithm; we compared their outcomes of mortality, and cardiac and neurologic complications with those of the general population using multivariable logistic regression models. Results: Compared to the general population (n = 439,977), the Chinese population (n = 15,208) was older (mean age 44.2 vs 40.6 years, P < 0.001) and the South Asian population (n = 46,333) was younger (39.2 years, P < 0.001). The Chinese population had a higher 30-day mortality (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.61) and more hospitalization or emergency department visits (OR, 1.14; 95% CI, 1.09-1.28), with a trend toward a higher incidence of cardiac complications (OR, 1.03; 95% CI, 0.87-1.12) and neurologic complications (OR, 1.23; 95% CI, 0.96-1.58). South Asians had a lower 30-day mortality (OR, 0.88; 95% CI, 0.78-0.98) but a higher incidence of hospitalization or emergency department visits (OR, 1.17; 95% CI, 1.14-1.20) with a trend toward a lower incidence of cardiac complications (OR, 0.76; 95% CI, 0.67-0.87) and neurologic complications (OR, 0.89; 95% CI, 0.73-1.09). There was also a significant difference in these outcomes between wave 1, 2 and 3, with a greater mortality in all groups in waves 2 and 3. Conclusions: Ethnicity continues to be an important determinant of mortality, cardiac and neurologic outcomes, and healthcare use among patients with COVID-19, requiring further studies to understand factors driving these differences.

Contexte: Nous avons déjà présenté les issues cliniques cardiaques et neurologiques chez les Ontariens de descendance chinoise ou sud-asiatique pour la première vague de la pandémie de COVID-19, mais les données au sujet des vagues ultérieures n'avaient pas encore été analysées. Nous présentons ici une prolongation de cette étude de cohortes pour la seconde et la troisième vague de COVID-19. Méthodologie: Notre analyse porte sur des adultes ontariens ayant obtenu un résultat positif à un test de COVID-19 par réaction en chaîne de la polymérase entre le 1er janvier 2020 et le 30 juin 2021. Un algorithme validé pour l'analyse des noms de famille a été utilisé pour isoler les sujets de descendance chinoise ou sud-asiatique, et leur taux de mortalité de même que les complications cardiaques et neurologiques ont été comparés à ceux de la population générale à l'aide de modèles de régression logistique multivariée. Résultats: En comparaison de la population générale (n = 439 977), les personnes de descendance chinoise (n = 15 208) se sont révélées plus âgées (âge moyen de 44,2 ans contre 40,6 ans, P < 0,001), tandis que les personnes de descendance sud-asiatique (n = 46 333) étaient plus jeunes (39,2 ans, P < 0,001). Dans la population de descendance chinoise, le taux de mortalité après 30 jours était plus élevé (rapport de cotes [RC] de 1,44; intervalle de confiance [IC] à 95 % de 1,28 à 1,61), et davantage d'hospitalisations ou de consultations aux urgences sont survenues (RC de 1,14; IC à 95 % de 1,09 à 1,28). L'incidence de complications cardiaques (RC de 1,03; IC à 95 % de 0,87 à 1,12) et de complications neurologiques (RC de 1,23; IC à 95 % de 0,96 à 1,58) avait également tendance à être plus élevée. Chez les personnes de descendance sud-asiatique, le taux de mortalité après 30 jours était plus faible (RC de 0,88; IC à 95 % de 0,78 à 0,98), mais l'incidence d'hospitalisations ou de consultations aux urgences était plus élevée (RC de 1,17; IC à 95 % de 1,14 à 1,20). Elles présentaient également une tendance vers une plus faible incidence de complications cardiaques (RC de 0,76; IC à 95 % de 0,67 à 0,87) et de complications neurologiques (RC de 0,89; IC à 95 % de 0,73 à 1,09). Des différences significatives ont également été observées pour ces paramètres entre les vagues 1, 2 et 3 de la maladie, et le taux de mortalité était plus élevé pour tous les groupes des vagues 2 et 3. Conclusions: L'origine ethnique demeure un déterminant important de la mortalité, des issues cliniques cardiaques et neurologiques ainsi que de l'utilisation des ressources en santé chez les patients atteints de la COVID-19. D'autres études sont toutefois nécessaires pour mieux comprendre les facteurs qui expliquent ces différences.

Features of Inflammatory Heart Reactions Following mRNA COVID-19 Vaccination at a Global Level.

Myocarditis and pericarditis may constitute adverse reactions of mRNA coronavirus disease 2019 (COVID-19) vaccines. This study aimed to document these reactions and to assess the association with patient sex and age. This is as an observational retrospective study using a case-non-case design (also called disproportionality study) on inflammatory heart reactions reported with mRNA COVID-19 vaccines within the World Health Organization (WHO) global safety database (VigiBase), up to June 30, 2021. Results are expressed using reporting odds ratios (RORs) and their 95% confidence interval (95% CI). Of 716,576 reports related to mRNA COVID-19 vaccines, 2,277 were cases of inflammatory heart reactions, including 1241 (55%) myocarditis and 851 (37%) pericarditis. The main age group was 18-29 years (704, 31%), and mostly male patients (1,555, 68%). Pericarditis onset was delayed compared with myocarditis with a median time to onset of 8 (3-21) vs. 3 (2-6) days, respectively (P = 0.001). Regarding myocarditis, an important disproportionate reporting was observed in adolescents (ROR, 22.3, 95% CI 19.2-25.9) and in 18-29 years old (ROR, 6.6, 95% CI 5.9-7.5) compared with older patients, as well as in male patients (ROR, 9.4, 95% CI 8.3-10.6). Reporting rate of myocarditis was increased in young adults and adolescents. Inflammatory heart reactions may rarely occur shortly following mRNA COVID-19 vaccination. Although an important disproportionate reporting of myocarditis was observed among adolescents and young adults, particularly in male patients, reporting rates support a very rare risk, that does not seem to compromise the largely positive benefit-risk balance of these vaccines. Furthermore, this study confirmed the value of disproportionality analyses for estimation of relative risks among subgroups of patients.

Computational Fluid Dynamics Optimization of an Extraoral Vacuum Aerosol Cup for Airborne Disease Control in Dental Offices

Graphic abstract Droplet and aerosol transmission of COVID-19 are the most important concerns in dental clinics, due to the generation of large amounts of infected aerosol and droplets mixed with patient’s saliva during the procedures. The current approach to prevent airborne disease transmission is an extraoral aerosol suction unit: a stand-alone vacuum module with a segmented arm and cup. Despite the need for disease control in dental offices, these units are rarely seen due to the loud noise produced by vacuum, bulky size, and high cost. This paper describes the aerodynamic design optimization of an affordable, 3D printable, Extraoral Vacuum Aerosol Cup (EVAC) that can be directly connected to existing standard 7/16″ central vacuum high-volume evacuator (HVE) valves used for intraoral saliva absorption in a dental office. These HVEs are typically unsuitable for extraoral suction due to their low vacuum force. However, they can be used for extraoral suction, if the cup attachment is aerodynamically optimized for maximum suction efficiency. Fifteen different designs of EVAC are proposed and their suction processes were simulated with computational fluid dynamics. Droplets of various sizes are released to mimic the droplets produced during dental operation. The suction performances of EVACs with different sizes and shapes were compared to find out the designs with optimal performance. Prototypes of the optimized EVAC are 3D printed and tested at a dental office. Development and manufacturing of such a device will largely reduce the COVID-19 infection risk, thus improving the safety protection for both patients and doctors at dental offices.

Night shift schedule alters endogenous regulation of circulating cytokines.

Night shift work is a risk factor for viral infection, suggesting that night shift schedules compromise host defense mechanisms. Prior studies have investigated changes in the temporal profiles of circulating cytokines important for priming and restraining the immune response to infectious challenges from night shift work, but not by way of a 24-h constant routine of continuous wakefulness devoid of behavioral or environmental influences. Hence the true endogenous pattern of cytokines, and the combined effect of sleep loss and circadian misalignment on these cytokines remains unknown. Here, 14 healthy young men and women underwent three days of either a simulated night shift or a simulated day shift schedule under dim light in a controlled in-laboratory environment. This was followed by a 24-h constant routine protocol during which venous blood was collected at 3-h intervals. Those who had been in the night shift schedule showed lower mean circulating TNF-α (t13 = -6.03, p < 0.001), without any significant differences in IL-1ß, IL-8 and IL-10, compared with those who had been in the day shift (i.e., control) schedule. Furthermore, circulating IL-6 increased with time awake in both shift work conditions (t13 = 6.03, p < 0.001), such that temporal changes in IL-6 were markedly shifted relative to circadian clock time in the night shift condition. These results indicate that night shift work compromises host defense by creating cytokine conditions that initially impede anti-viral immunity (lower TNF-α) and may eventually promote autoimmunity (mistimed rise in IL-6).

COVID-19 and its Cardiac and Neurological Complications among Ontario Visible Minorities.

BACKGROUND: Due to lack of data on the epidemiology, cardiac, and neurological complications among Ontario visible minorities (Chinese and South Asians) affected by coronavirus disease (COVID-19), this population-based retrospective study was undertaken to study them systematically. METHODS: From January 1, 2020 to September 30, 2020 using the last name algorithm to identify Ontario Chinese and South Asians who were tested positive by PCR for COVID-19, their demographics, cardiac, and neurological complications including hospitalization and emergency visit rates were analyzed compared to the general population. RESULTS: Chinese (N = 1,186) with COVID-19 were found to be older (mean age 50.7 years) compared to the general population (N = 42,547) (mean age 47.6 years) (p < 0.001), while South Asians (N = 3,459) were younger (age of 42.1 years) (p < 0.001). The 30-day crude rate for cardiac complications among Chinese was 169/10,000 (p = 0.069), while for South Asians, it was 64/10,000 (p = 0.008) and, for the general population, it was 112/10,000. For neurological complications, the 30-day crude rate for Chinese was 160/10,000 (p < 0.001); South Asians was 40/10,000 (p = 0.526), and general population was 48/10,000. The 30-day all-cause mortality rate was significantly higher for Chinese at 8.1% vs 5.0% for the general population (p < 0.001), while it was lower in South Asians at 2.1% (p < 0.001). CONCLUSIONS: Chinese and South Asians in Ontario affected by COVID-19 during the first wave of the pandemic were found to have a significant difference in their demographics, cardiac, and neurological outcomes.

Taskforce report on the diagnosis and clinical management of COVID-19 associated pulmonary aspergillosis.

PURPOSE: Invasive pulmonary aspergillosis (IPA) is increasingly reported in patients with severe coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU). Diagnosis and management of COVID-19 associated pulmonary aspergillosis (CAPA) are challenging and our aim was to develop practical guidance. METHODS: A group of 28 international experts reviewed current insights in the epidemiology, diagnosis and management of CAPA and developed recommendations using GRADE methodology. RESULTS: The prevalence of CAPA varied between 0 and 33%, which may be partly due to variable case definitions, but likely represents true variation. Bronchoscopy and bronchoalveolar lavage (BAL) remain the cornerstone of CAPA diagnosis, allowing for diagnosis of invasive Aspergillus tracheobronchitis and collection of the best validated specimen for Aspergillus diagnostics. Most patients diagnosed with CAPA lack traditional host factors, but pre-existing structural lung disease and immunomodulating therapy may predispose to CAPA risk. Computed tomography seems to be of limited value to rule CAPA in or out, and serum biomarkers are negative in 85% of patients. As the mortality of CAPA is around 50%, antifungal therapy is recommended for BAL positive patients, but the decision to treat depends on the patients' clinical condition and the institutional incidence of CAPA. We recommend against routinely stopping concomitant corticosteroid or IL-6 blocking therapy in CAPA patients. CONCLUSION: CAPA is a complex disease involving a continuum of respiratory colonization, tissue invasion and angioinvasive disease. Knowledge gaps including true epidemiology, optimal diagnostic work-up, management strategies and role of host-directed therapy require further study.

Integrated photothermal decontamination device for N95 respirators.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the COVID-19 global pandemic has infected over 25 million people worldwide and resulted in the death of millions. The COVID-19 pandemic has also resulted in a shortage of personal protective equipment (PPE) in many regions around the world, particularly in middle- and low-income countries. The shortages of PPE, such as N95 respirators, is something that will persist until an effective vaccine is made available. Thus, devices that while being easy to operate can also be rapidly deployed in health centers, and long-term residences without the need for major structural overhaul are instrumental to sustainably use N95 respirators. In this report, we present the design and validation of a decontamination device that combines UV-C & B irradiation with mild-temperature treatment. The device can decontaminate up to 20 masks in a cycle of < 30 min. The decontamination process did not damage or reduce the filtering capacity of the masks. Further, the efficacy of the device to eliminate microbes and viruses from the masks was also evaluated. The photothermal treatment of our device was capable of eradicating > 99.9999% of the bacteria and > 99.99% of the virus tested.

Redefining Cardiac Biomarkers in Predicting Mortality of Inpatients With COVID-19.

The prognostic power of circulating cardiac biomarkers, their utility, and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multicentered retrospective study, we enrolled 3219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effects Cox model, after adjusting for age, sex, and comorbidities, the adjusted hazard ratio of 28-day mortality for hs-cTnI (high-sensitivity cardiac troponin I) was 7.12 ([95% CI, 4.60-11.03] P<0.001), (NT-pro)BNP (N-terminal pro-B-type natriuretic peptide or brain natriuretic peptide) was 5.11 ([95% CI, 3.50-7.47] P<0.001), CK (creatine phosphokinase)-MB was 4.86 ([95% CI, 3.33-7.09] P<0.001), MYO (myoglobin) was 4.50 ([95% CI, 3.18-6.36] P<0.001), and CK was 3.56 ([95% CI, 2.53-5.02] P<0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 19%-50% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoff values of these biomarkers might be much lower than the current reference standards. These findings can assist in better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19-associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials.

Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion.

PURPOSE: Invasive pulmonary aspergillosis is increasingly reported in patients with influenza admitted to the intensive care unit (ICU). Classification of patients with influenza-associated pulmonary aspergillosis (IAPA) using the current definitions for invasive fungal diseases has proven difficult, and our aim was to develop case definitions for IAPA that can facilitate clinical studies. METHODS: A group of 29 international experts reviewed current insights into the epidemiology, diagnosis and management of IAPA and proposed a case definition of IAPA through a process of informal consensus. RESULTS: Since IAPA may develop in a wide range of hosts, an entry criterion was proposed and not host factors. The entry criterion was defined as a patient requiring ICU admission for respiratory distress with a positive influenza test temporally related to ICU admission. In addition, proven IAPA required histological evidence of invasive septate hyphae and mycological evidence for Aspergillus. Probable IAPA required the detection of galactomannan or positive Aspergillus culture in bronchoalveolar lavage (BAL) or serum with pulmonary infiltrates or a positive culture in upper respiratory samples with bronchoscopic evidence for tracheobronchitis or cavitating pulmonary infiltrates of recent onset. The IAPA case definitions may be useful to classify patients with COVID-19-associated pulmonary aspergillosis (CAPA), while awaiting further studies that provide more insight into the interaction between Aspergillus and the SARS-CoV-2-infected lung. CONCLUSION: A consensus case definition of IAPA is proposed, which will facilitate research into the epidemiology, diagnosis and management of this emerging acute and severe Aspergillus disease, and may be of use to study CAPA.

In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19.

Statins are lipid-lowering therapeutics with favorable anti-inflammatory profiles and have been proposed as an adjunct therapy for COVID-19. However, statins may increase the risk of SARS-CoV-2 viral entry by inducing ACE2 expression. Here, we performed a retrospective study on 13,981 patients with COVID-19 in Hubei Province, China, among which 1,219 received statins. Based on a mixed-effect Cox model after propensity score-matching, we found that the risk for 28-day all-cause mortality was 5.2% and 9.4% in the matched statin and non-statin groups, respectively, with an adjusted hazard ratio of 0.58. The statin use-associated lower risk of mortality was also observed in the Cox time-varying model and marginal structural model analysis. These results give support for the completion of ongoing prospective studies and randomized controlled trials involving statin treatment for COVID-19, which are needed to further validate the utility of this class of drugs to combat the mortality of this pandemic.

Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19.

RATIONALE: Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension. OBJECTIVE: To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19. METHODS AND RESULTS: This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55-68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57-69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19-0.92]; P=0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15-0.89]; P=0.03). Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12-0.70]; P=0.01) in patients with COVID-19 and coexisting hypertension. CONCLUSIONS: Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.

The Science Underlying COVID-19: Implications for the Cardiovascular System.

The coronavirus disease 2019 (COVID-19) pandemic has affected health and economy worldwide on an unprecedented scale. Patients have diverse clinical outcomes, but those with preexisting cardiovascular disease, hypertension, and related conditions incur disproportionately worse outcome. The high infectivity of severe acute respiratory syndrome coronavirus 2 is in part related to new mutations in the receptor binding domain, and acquisition of a furin cleavage site in the S-spike protein. The continued viral shedding in the asymptomatic and presymptomatic individuals enhances its community transmission. The virus uses the angiotensin converting enzyme 2 receptor for internalization, aided by transmembrane protease serine 2 protease. The tissue localization of the receptors correlates with COVID-19 presenting symptoms and organ dysfunction. Virus-induced angiotensin converting enzyme 2 downregulation may attenuate its function, diminish its anti-inflammatory role, and heighten angiotensin II effects in the predisposed patients. Lymphopenia occurs early and is prognostic, potentially associated with reduction of the CD4+ and some CD8+ T cells. This leads to imbalance of the innate/acquired immune response, delayed viral clearance, and hyperstimulated macrophages and neutrophils. Appropriate type I interferon pathway activation is critical for virus attenuation and balanced immune response. Persistent immune activation in predisposed patients, such as elderly adults and those with cardiovascular risk, can lead to hemophagocytosis-like syndrome, with uncontrolled amplification of cytokine production, leading to multiorgan failure and death. In addition to the airways and lungs, the cardiovascular system is often involved in COVID-19 early, reflected in the release of highly sensitive troponin and natriuretic peptides, which are all extremely prognostic, in particular, in those showing continued rise, along with cytokines such as interleukin-6. Inflammation in the vascular system can result in diffuse microangiopathy with thrombosis. Inflammation in the myocardium can result in myocarditis, heart failure, cardiac arrhythmias, acute coronary syndrome, rapid deterioration, and sudden death. Aggressive support based on early prognostic indicators with expectant management can potentially improve recovery. Appropriate treatment for heart failure, arrhythmias, acute coronary syndrome, and thrombosis remain important. Specific evidence-based treatment strategies for COVID-19 will emerge with ongoing global collaboration on multiple approaches being evaluated. To protect the wider population, antibody testing and effective vaccine will be needed to make COVID-19 history.