Characteristics of Cardiac Abnormalities in Pediatric Patients With Acute COVID-19.

Introduction Coronavirus disease 2019 (COVID-19) is known to cause cardiac abnormalities in adults. Cardiac abnormalities are well-described in multisystem inflammatory syndrome in children, but effects in children with acute COVID-19 are less understood. In this multicenter study, we assessed the cardiac effects of acute COVID-19 among hospitalized children (<21 years) admitted to three large healthcare systems in New York City. Methods We performed a retrospective observational study. We examined electrocardiograms, echocardiograms, troponin, or B-type natriuretic peptides. Results Of 317 admitted patients, 131 (41%) underwent cardiac testing with 56 (43%) demonstrating cardiac abnormalities. Electrocardiogram abnormalities were the most common (46/117 patients (39%)), including repolarization abnormalities and QT prolongation. Elevated troponin occurred in 14/77 (18%) patients and B-type natriuretic peptide in 8/39 (21%) patients. Ventricular dysfunction was identified in 5/27 (19%) patients with an echocardiogram, all of whom had elevated troponin. Ventricular dysfunction resolved by first outpatient follow-up. Conclusion Electrocardiogram and troponin can assist clinicians in identifying children at risk for cardiac injury in acute COVID-19.

Strain in children with MIS-C and acute COVID-19.

Context: Cardiac injury has been described in both acute COVID-19 and the multisystem inflammatory syndrome in children (MIS-C). Echocardiographic strain has been shown to be a sensitive measure of systolic function. Aims: We sought to describe strain findings in both the groups on initial presentation and follow-up. Settings and Design: A retrospective study analyzing echocardiograms of all patients presenting with acute COVID-19 infection and MIS-C at our institution between March 2020 and December 2020 was performed. Subjects and Methods: TOMTEC software was used for strain analysis in both the study groups (COVID-19 and MIS-C) and age-matched healthy controls. Strain was correlated with LV ejection fraction (EF) and serum troponin levels. Results: Forty-five patients (34 - MIS-C and 11 - COVID-19) met the inclusion criteria. There was a statistically significant decrease in LV longitudinal strain (P < 0.001), LV circumferential strain (P < 0.001), and left atrial strain (P = 0.014) in the MIS-C group when compared to the control group. There was a statistically significant decrease in LV longitudinal strain (P = 0.028) in the acute COVID-19 group. All patients with abnormal left ventricular EF (LVEF) had abnormal strain. However, 14 (41%) patients in the MIS-C group and 3 (27%) in the acute COVID-19 group had preserved LVEF but abnormal strain. There was a significant correlation with LV longitudinal strain (P = 0.005) and LVEF (P = 0.002) and troponin in patients with MIS-C. Abnormal strain persisted in one-third of patients in the MIS-C and acute COVID-19 groups on outpatient follow-up. Conclusions: Patients with MIS-C and acute COVID-19 can develop myocardial dysfunction as seen by abnormal strain. LV longitudinal strain correlates with cardiac injury as measured by serum troponin in patients with MIS-C. Strain may provide an additional tool in detecting subtle myocardial dysfunction. It can be routinely employed at diagnosis and at follow-up evaluation of these patients.

Potential for Further Mismanagement of Fever During COVID-19 Pandemic: Possible Causes and Impacts.

Fever remains an integral part of acute infectious diseases management, especially for those without effective therapeutics, but the widespread myths about "fevers" and the presence of confusing guidelines from different agencies, which have heightened during the coronavirus disease 2019 (COVID-19) pandemic and are open to alternate interpretation, could deny whole populations the benefits of fever. Guidelines suggesting antipyresis for 37.8-39°C fever are concerning as 39°C boosts the protective heat-shock and immune response (humoral, cell-mediated, and nutritional) whereas ≥40°C initiates/enhances the antiviral responses and restricts high-temperature adapted pathogens, e.g., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), strains of influenza, and measles. Urgent attention is accordingly needed to address the situation because of the potential public health consequences of the existence of conflicting guidelines in the public domain. We have in this article attempted to restate the benefits of fever in disease resolution, dispel myths, and underline the need for alignment of national treatment guidelines with that of the WHO, to promote appropriate practices and reduce the morbidity and mortality from infectious diseases, such as COVID-19.

Higher BCG-induced trained immunity prevalence predicts protection from COVID-19: Implications for ongoing BCG trials.

Endeavors to identify potentially protective variables for COVID-19 impact on certain populations have remained a priority. Multiple attempts have been made to attribute the reduced COVID-19 impact on populations to their Bacillus-Calmette-Guérin (BCG) vaccination coverage ignoring the fact that the effect of childhood BCG vaccination wanes within 5 years while most of the COVID-19 cases and deaths have occurred in aged with comorbidities. Since the supposed protection being investigated could come from heterologous 'trained immunity' (TI) conferred by exposure to Mycobacterium spp. (i.e., environmental and BCG), it is argued that the estimates of the prevalence of TI in populations currently available as latent tuberculosis infection (LTBI) prevalence would be a better variable to evaluate such assertions. Indeed, when we analyze the European populations (24), and erstwhile East and West Germany populations completely disregarding their BCG vaccination coverage, the populations with higher TI prevalence consistently display reduced COVID-19 impact as compared to their lower TI prevalence neighbors. The TI estimates of the populations not the BCG coverage per se, negatively correlated with pandemic phase-matched COVID-19 incidences (r(24): -0.79 to -0.57; p-value < .004), mortality (r(24): -0.63 to -0.45; p-value < .03), and interim case fatality rates (i-CFR) data. To decisively arrive at dependable conclusions about the potential protective benefit gained from BCG vaccination in COVID-19, the ongoing or planned randomized controlled trials should consciously consider including measures of TI as: (a) all individuals immunized do not respond equally, (b) small study groups from higher background TI could fail to indicate any protective effect.

Potential for Further Mismanagement of Fever During COVID-19 Pandemic: Possible Causes and Impacts

Fever remains an integral part of acute infectious diseases management, especially for those without effective therapeutics, but the widespread myths about “fevers” and the presence of confusing guidelines from different agencies, which have heightened during the coronavirus disease 2019 (COVID-19) pandemic and are open to alternate interpretation, could deny whole populations the benefits of fever. Guidelines suggesting antipyresis for 37.8–39°C fever are concerning as 39°C boosts the protective heat-shock and immune response (humoral, cell-mediated, and nutritional) whereas ≥40°C initiates/enhances the antiviral responses and restricts high-temperature adapted pathogens, e.g., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), strains of influenza, and measles. Urgent attention is accordingly needed to address the situation because of the potential public health consequences of the existence of conflicting guidelines in the public domain. We have in this article attempted to restate the benefits of fever in disease resolution, dispel myths, and underline the need for alignment of national treatment guidelines with that of the WHO, to promote appropriate practices and reduce the morbidity and mortality from infectious diseases, such as COVID-19.

Role of toll-like receptors in modulation of cytokine storm signaling in SARS-CoV-2-induced COVID-19.

Balanced immune regulation is crucial for recognizing an invading pathogen, its killing, and elimination. Toll-like receptors (TLRs) are the key regulators of the innate immune system. It helps in identifying between self and nonself-molecule and eventually eliminates the nonself. Endosomal TLR, mainly TLR3, TLR7, TLR8, and membrane-bound TLR4, has a role in the induction of cytokine storms. TLR7/8 recognizes the ssRNA SARS-COV-2 and when it replicates to dsRNA, it is recognized by TLR3 and drives the TRIF-mediated inflammatory signaling like NF-κB, MAPK. Such signaling leads to significant transcription and translation of pro-inflammatory genes, releasing inflammatory molecules into the systemic circulation, causing an imbalance in the system. So, whenever an imbalance occurs, a surge in the pro-inflammatory mediators is observed in the blood, including cytokines like interleukin (IL)-2, IL-4, IL-6, IL-1ß, IL-8, interferon (IFN)-γ, tumor necrosis factor (TNF)-α. IL-6 and IL-1ß are one of the driving factors for bringing the cytokine storm into the systemic circulation, which migrates into the other organs, causing multiple organ failures leading to the death of the individual with severe illness.

Clinical Features and Outcome of Stroke with COVID-19. COVID-19 Stroke Study Group (CSSG), India.

BACKGROUND AND PURPOSE: Occurrence of stroke has been reported among patients with COVID-19. The present study compares clinical features and outcomes of stroke patients with and without COVID-19. METHODS: The COVID-19 Stroke Study Group (CSSG) is a multicentric study in 18 sites across India to observe and compare the clinical characteristics of patients with stroke admitted during the current pandemic period and a similar epoch in 2019. The present study reports patients of stroke with and without COVID-19 (CoVS and non-CoVS, respectively) seen between February 2020 and July 2020. Demographic, clinical, treatment, and outcome details of patients were collected. RESULTS: The mean age and gender were comparable between the two groups. CoVS patients had higher stroke severity and extent of cerebral involvement on imaging. In-hospital complications and death were higher among CoVS patients (53.06% vs. 17.51%; P < 0.001) and (42.31% vs. 7.6%; P < 0.001), respectively. At 3 months, higher mortality was observed among CoVS patients (67.65% vs. 13.43%; P < 0.001) and good outcome (modified Rankin score [mRS]: 0-2) was seen more often in non-CoVS patients (68.86% vs. 33.33%; P < 0.001). The presence of COVID-19 and baseline stroke severity were independent predictors of mortality. CONCLUSIONS: CoVS is associated with higher severity, poor outcome, and increased mortality. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and baseline stroke severity are independent predictors of mortality.

Nutritional Immunity, Zinc Sufficiency, and COVID-19 Mortality in Socially Similar European Populations.

The impact of zinc (Zn) sufficiency/supplementation on COVID-19-associated mortality and incidence (SARS-CoV-2 infections) remains unknown. During an infection, the levels of free Zn are reduced as part of "nutritional immunity" to limit the growth and replication of pathogen and the ensuing inflammatory damage. Considering its key role in immune competency and frequently recorded deficiency in large sections of different populations, Zn has been prescribed for both prophylactic and therapeutic purposes in COVID-19 without any corroborating evidence for its protective role. Multiple trials are underway evaluating the effect of Zn supplementation on COVID-19 outcome in patients getting standard of care treatment. However, the trial designs presumably lack the power to identify negative effects of Zn supplementation, especially in the vulnerable groups of elderly and patients with comorbidities (contributing 9 out of 10 deaths; up to >8,000-fold higher mortality). In this study, we have analyzed COVID-19 mortality and incidence (case) data from 23 socially similar European populations with comparable confounders (population: 522.47 million; experiencing up to >150-fold difference in death rates) and at the matching stage of the pandemic (March 12 to June 26, 2020; first wave of COVID-19 incidence and mortality). Our results suggest a positive correlation between populations' Zn-sufficiency status and COVID-19 mortality [r (23): 0.7893-0.6849, p-value < 0.0003] as well as incidence [r (23):0.8084-0.5658; p-value < 0.005]. The observed association is contrary to what would be expected if Zn sufficiency was protective in COVID-19. Thus, controlled trials or retrospective analyses of the adverse event patients' data should be undertaken to correctly guide the practice of Zn supplementation in COVID-19.

Clinical profile and outcome of non-COVID strokes during pandemic and the pre pandemic period: COVID-Stroke Study Group (CSSG) India.

BACKGROUND: As the health systems around the world struggled to meet the challenges of COVID-19 pandemic, care of many non-COVID emergencies was affected. AIMS: The present study examined differences in the diagnosis, evaluation and management of stroke patients during a defined period in the ongoing pandemic in 2020 when compared to a similar epoch in year 2019. METHODS: The COVID stroke study group (CSSG) India, included 18 stroke centres spread across the country. Data was collected prospectively between February and July 2020 and retrospectively for the same period in 2019. Details of demographics, stroke evaluation, treatment, in-hospital and three months outcomes were collected and compared between these two time points. RESULTS: A total of 2549 patients were seen in both study periods; 1237 patients (48.53%) in 2019 and 1312 (51.47%) in 2020. Although the overall number of stroke patients and rates of thrombolysis were comparable, a significant decline was observed in the month of April 2020, during the initial period of the pandemic and lockdown. Endovascular treatment reduced significantly and longer door to needle and CT to needle times were observed in 2020. Although mortality was higher in 2020, proportion of patients with good outcome were similar in both the study periods. CONCLUSIONS: Although stroke admissions and rates of thrombolysis were comparable, some work flow metrics were delayed, endovascular stroke treatment rates declined and mortality was higher during the pandemic study period. Reorganization of stroke treatment pathways during the pandemic has likely improved the stroke care delivery across the globe.

"Trained immunity" from Mycobacterium spp. exposure or BCG vaccination and COVID-19 outcomes.

Protective variables for Coronavirus Disease 2019 (COVID-19) are unknown. "Trained immunity" of the populace as a result of Bacille Calmette-Guérin (BCG) vaccination policy implementation and coverage had been suggested to be one of the factors responsible for the differential impact of COVID-19 on different countries. Several trials are underway to evaluate the potential protective role of BCG vaccination in COVID-19. However, the lack of clarity on the use of appropriate controls concerning the measures of "trained immunity" or the heterologous cell-mediated immunity conferred by BCG vaccination has been a cause of concern leading to more confusion as exemplified by a recently concluded trial in Israel that failed to find any protective correlation with regard to BCG vaccination. Whereas, when we analyze the COVID-19 epidemiological data of European countries without any regard for BCG vaccination policy but with similar age distribution, comparable confounding variables, and the stage of the pandemic, the prevalence of tuberculin immunoreactivity-a measure of cell-mediated immunity persistence as a result of Mycobacterium spp. (including BCG vaccine) exposure of the populations-is found consistently negatively correlated with COVID-19 infections and mortality. We seek to draw attention toward the inclusion of controls for underlying "trained immunity" and heterologous cell-mediated immunity prevalence that may be preexisting or resulting from the intervention (e.g., BCG vaccine) in such trials to arrive at more dependable conclusions concerning potential benefit from them.

Cardiac Findings in Pediatric Patients With Multisystem Inflammatory Syndrome in Children Associated With COVID-19.

BACKGROUND: The overall severity of cardiac disease secondary to acute SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) infection in children appears to be much lower when compared with adults. However, the newly described multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19) has been associated with cardiac complications. METHODS: We reviewed the clinical course and cardiac testing results in pediatric patients hospitalized with MIS-C at 2 large hospital systems in the New York City metropolitan area over a 3-month period. RESULTS: Of the 33 patients (median age 2.8 years) in the study cohort, 24 (73%) had at least one abnormality in cardiac testing: abnormal electrocardiogram (48%), elevated brain natriuretic peptide (43%), abnormal echocardiogram (30%), and/or elevated troponin (21%). Electrocardiogram and echocardiogram abnormalities all resolved by the 2-week outpatient follow-up cardiology visit. CONCLUSION: While 73% of pediatric patients with MIS-C had evidence of abnormal cardiac testing on hospital admission in our study, all cardiac testing was normal by outpatient hospital discharge follow-up. Cardiac screening tests should be performed in all patients diagnosed with MIS-C given the high rate of abnormal cardiac findings in our study cohort.