The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19

A pandemic of historic impact, coronavirus disease 2019 (COVID-19) has potential consequences on the cardiovascular health of millions of people who survive infection worldwide. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can infect the heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), the host cell receptor for the viral spike protein. Acute cardiac injury is a common extrapulmonary manifestation of COVID-19 with potential chronic consequences. This update provides a review of the clinical manifestations of cardiovascular involvement, potential direct SARS-CoV-2 and indirect immune response mechanisms impacting the cardiovascular system, and implications for the management of patients after recovery from acute COVID-19 infection.

COVID-19 and Cardiovascular Disease: From Bench to Bedside.

The Montreux definition of neonatal ARDS: biological and clinical background behind the description of a new entity

Importance Cardiac injury with attendant negative prognostic implications is common among patients hospitalized with coronavirus disease 2019 (COVID-19) infection. Whether cardiac injury, including myocarditis, also occurs with asymptomatic or mild-severity COVID-19 infection is uncertain. There is an ongoing concern about COVID-19–associated cardiac pathology among athletes because myocarditis is an important cause of sudden cardiac death during exercise. Observations Prior to relaxation of stay-at-home orders in the US, the American College of Cardiology’s Sports and Exercise Cardiology Section endorsed empirical consensus recommendations advising a conservative return-to-play approach, including cardiac risk stratification, for athletes in competitive sports who have recovered from COVID-19. Emerging observational data coupled with widely publicized reports of athletes in competitive sports with reported COVID-19–associated cardiac pathology suggest that myocardial injury may occur in cases of COVID-19 that are asymptomatic and of mild severity. In the absence of definitive data, there is ongoing uncertainty about the optimal approach to cardiovascular risk stratification of athletes in competitive sports following COVID-19 infection. Conclusions and Relevance This report was designed to address the most common questions regarding COVID-19 and cardiac pathology in athletes in competitive sports, including the extension of return-to-play considerations to discrete populations of athletes not addressed in prior recommendations. Multicenter registry data documenting cardiovascular outcomes among athletes in competitive sports who have recovered from COVID-19 are currently being collected to determine the prevalence, severity, and clinical relevance of COVID-19–associated cardiac pathology and efficacy of targeted cardiovascular risk stratification. While we await these critical data, early experiences in the clinical oversight of athletes following COVID-19 infection provide an opportunity to address key areas of uncertainty relevant to cardiology and sports medicine practitioners.

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Coronavirus Disease 2019 and the Athletic Heart: Emerging Perspectives on Pathology, Risks, and Return to Play.

Immune-related manifestations are increasingly recognized conditions in patients with COVID-19, with around 3,000 cases reported worldwide comprising more than 70 different systemic and organ-specific disorders. Although the inflammation caused by SARS-CoV-2 infection is predominantly centred on the respiratory system, some patients can develop an abnormal inflammatory reaction involving extrapulmonary tissues. The signs and symptoms associated with this excessive immune response are very diverse and can resemble some autoimmune or inflammatory diseases, with the clinical phenotype that is seemingly influenced by epidemiological factors such as age, sex or ethnicity. The severity of the manifestations is also very varied, ranging from benign and self-limiting features to life-threatening systemic syndromes. Little is known about the pathogenesis of these manifestations, and some tend to emerge within the first 2 weeks of SARS-CoV-2 infection, whereas others tend to appear in a late post-infectious stage or even in asymptomatic patients. As the body of evidence comprises predominantly case series and uncontrolled studies, diagnostic and therapeutic decision-making is unsurprisingly often based on the scarcely reported experience and expert opinion. Additional studies are required to learn about the mechanisms involved in the development of these manifestations and apply that knowledge to achieve early diagnosis and the most suitable therapy.

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Systemic and organ-specific immune-related manifestations of COVID-19.

Pediatric Critical Care Medicine www.pccmjournal.org 603 The authors reply: We thank Muñoz et al (1) for their letter discussing the recently published recommendations and definitions of pediatric acute respiratory distress syndrome (PARDS) from the Pediatric Acute Lung Injury Consensus Conference (PALICC) (2). We are pleased they consider the recommendations “breakthrough” but hope that clinicians will proceed with caution until external validation is completed. These recommendations, which were created to better assess and manage PARDS in children, are considered the groundwork for which further research is essential. The authors questioned the use of oxygenation index (OI) in the PARDS definition. The OI values used to define severity of PARDS were derived based on analyses of data from 397 children previously collected data from Children’s Hospital of Los Angeles (3) and the Pediatric Study Group, Australian and New Zealand Intensive Care Society (4), and then validated with data from 692 children collected from an additional datasets from other members of the PALICC members (5–9), as described in a supplemental article (10). Support for the relationship of OI to outcome in PARDS is also supplied by an independent dataset reported by Yehya et al (11) from Children’s Hospital of Philadelphia. Additional external validation would clearly be helpful, however, as would data identifying the day or time after the initial injury for which calculation of OI would be most predictive of outcome. Gabriela Ortega Cisternas Muñoz, MD, Natália Viu Degaspare, MD, Artur Figueiredo Delgado, MD, PhD, Werther Brunow de Carvalho, MD, PhD, Department of Pediatric Critical Care, Instituto da Criança da Faculdade de Medicina, São Paulo University, São Paulo, Brazil

What Will Be the Consensus of Pediatric Intensivists Regarding the Diagnosis of Pediatric Acute Respiratory Distress Syndrome

394 www.pccmjournal.org May 2015 • Volume 16 • Number 4 the original Starling model. In some diseases where the inflammatory response can increase the pulmonary capillary permeability (4), an elevated EVLW can be found in a patient with normal cardiovascular status. Monnet et al (5) suggest that the ratio of EVLW to GEDV may better discriminate between pulmonary edema caused by abnormal capillary permeability and left heart failure. Especially in patients with diastolic dysfunction, the edge between normovolemia and fluid overload may be very close. Sankar et al (6) showed that diastolic dysfunction evaluated by echocardiography in patients with positive fluid balance was associated to a higher mortality. Although troponin-T was not linked to predict diastolic dysfunction in an early moment (6), other biomarkers, such as brain natriuretic peptide, should be taken in consideration (7). The elaboration of a protocol including biomarkers, echocardiography, and clinical parameters (noninvasive methods) could be useful in the majority of patients, and in very critical condition (persistent unresponsiveness of fluid challenge or higher dosage of vasoactive drugs), the sequential measurement of EVLW/GEDV would be necessary. The precise estimative of diastolic volume and CO has been looking forward in PICU for long time, but adverse effects of invasive monitoring and difficulties related to the methods turned real-time procedures (main clinical data and bedside echocardiography) more realistic. The best association of all relevant parameters is still pending. The authors have disclosed that they do not have any potential conflicts of interest.

Natalia Viu Degaspare

Papers

What Will Be the Consensus of Pediatric Intensivists Regarding the Diagnosis of Pediatric Acute Respiratory Distress Syndrome

Invasive measurement of global end-diastolic volume: is it possible to add any data besides clinical parameters?

Comment regarding pediatric severe acute respiratory syndrome coronavirus 2: clinical presentation, infectivity, and immune responses.