key: cord-0012004-74sca83t
authors: Du, Yingzhen; Wang, Xi; Chang, Christopher; Zhu, Pingjun; Tu, Lei; Hu, Qinyong; Jin, Yang; Xu, Guogang
title: Reply to Tsolaki and Zakynthinos: Are Patients with COVID-19 Dying of or with Cardiac Injury?
date: 2020-07-15
journal: Am J Respir Crit Care Med
DOI: 10.1164/rccm.202004-1156le
sha: 0787135be064ed8b93b0e271563a5471652c6907
doc_id: 12004
cord_uid: 74sca83t

nan

In our study, the lactate dehydrogenase, creatinine kinase, and aspartate aminotransferase levels analyzed were obtained on admission. In an isolation unit, where physical examination is difficult to perform because of donning of protective gear, laboratory findings and chest computed tomographic (CT) scans are crucial tools for disease monitoring and can help identify early risk factors for mortality in patients with coronavirus disease (COVID-19) (1, 2) .

The question of how acute cardiac injury should be assessed is debatable. However, according to chapter 2 of the Fourth Universal Definition of Myocardial Infarction published in 2018, "Universal Definitions of Myocardial Injury and Myocardial Infarction," myocardial injury is defined as elevated cardiac troponin values with at least one value above the 99th percentile upper reference limit (3). These are the same criteria used in similar recently published papers on COVID-19 (4, 5) . The 44.7% of our patients with acute cardiac injury rely on TnI (troponin I) or TnT (troponin T) measured during patients' hospitalization, whereas other biomarkers, such as CK-MB (creatine kinase MB isoform), NT-proBNP (N-terminal prohormone of brain natriuretic peptide), and BNP, are less sensitive and less specific. Acute cardiac injury was reported in 59% of nonsurvivors in Huang and colleagues' report, which is consistent with our findings (5). It should be clear that cardiac injury is a depictive diagnosis, the spectrum of which ranges from mild injury to myocardial infarction. Various clinical entities may accompany these myocardial abnormalities, such as ventricular tachyarrhythmia, heart failure, kidney disease, hypotension and/or shock, hypoxemia, and anemia (3). Therefore, cardiac injury cannot always be considered as the main driver of death, which is why it was not included in Table 1 of our paper but instead as a complication reflected by TnI or TnT levels as shown in Table 5 of our paper.

The mechanism of cardiac injury in patients with COVID-19 is still unclear. There are several possibilities: 1) The role of cytokine storm has been previously shown, wherein IL-1b, IL-6, IL-12, IP-10 (IFN-g-induced protein 10), and MCP-1 (monocyte chemoattractant protein 1) levels are increased in COVID-19 (5, 6). 2) Oudit and colleagues showed that downregulation of ACE2 (angiotensinconverting enzyme 2) is associated with the degree of macrophage infiltration after myocardial infection. It is speculated that downregulation of ACE2 expression secondary to viral infection may be related to cardiac insufficiency (7) . 3) Long-term bed rest can lead to coagulation system activation, secondary intravascular microthrombosis, and pulmonary embolism. 4) Hypoxemia, pulmonary vasospasm, inflammation and hypercapnia, and secondary transient pulmonary hypertension can lead to right heart flow limitations. Cardiomyocyte ischemia or hypoxia leads to impaired left heart function and aggravates pulmonary congestion. 5) Fever, anorexia, and hypoproteinemia can lead to increased pulmonary exudation, rendering the patient vulnerable to secondary infection by other pathogens, inducing multiple organ dysfunction.

Echocardiographic abnormalities observed in patients with COVID-19 included reduced cardiac systolic and diastolic function, stress myocardiopathy, and right heart dysfunction, which can result from right heart volume and/or pressure load related to increased pulmonary resistance, inappropriate mechanical ventilation, or volume overload. However, patients with severe COVID-19 have rapid changes in echocardiographic findings.

Increased cardiac dimension on CT imaging is insufficient to diagnose myocarditis in patients with COVID-19. The standard Dallas pathological criteria for the definition of myocarditis require that an inflammatory cellular infiltrate with or without associated myocyte necrosis be present on conventionally stained heart-tissue sections (8) . At present, there has not been autopsy evidence to indicate myocarditis, although a recent study showed the presence of few interstitial mononuclear inflammatory infiltrates. No other substantial myocardial damage has been found in the heart tissue of patients who died of COVID-19 (9) . Figure 1C of our paper is a CT image of a 23-year-old female patient who died of acute respiratory failure. The patient has a very small amount of right pleural effusion, but the CT image of the left lower pulmonary vessels is very clear, which does not show evidence of an increase in vascular pressure. There is no thickening of the blood vessels, and no perivascular exudation is seen. This patient had severe anemia with Hb 44 g/L but no increase in BNP. It is likely that the change in heart shadow seen on CT imaging is caused by anemia.

It should be noted that none of the patients had been on chloroquine, so this could not be the cause of the arrythmias observed in our patients. Perfusion markers such as low central venous oxygen saturation were not available for this study, but we agree that this would be useful information to obtain in future studies.

We thank Tsolaki and Zakynthinos again for their insightful comments. n Author disclosures are available with the text of this letter at www.atsjournals.org.

Clinical features of 85 fatal cases of COVID-19 from Wuhan: a retrospective observational study

Pathophysiology of Takotsubo syndrome

Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirusinfected pneumonia in Wuhan, China

New insights into the mechanisms involved in B-type natriuretic peptide elevation and its prognostic value in septic patients

Clinical features of 85 fatal cases of COVID-19 from Wuhan: a retrospective observational study

Clinical pathway for early diagnosis of COVID-19: updates from experience to evidence-based practice

Fourth universal definition of myocardial infarction

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Clinical characteristics of coronavirus disease 2019 in China

SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Copyright © 2020 by the American Thoracic Society Calibration Myths in the

For commercial usage and reprints

O'B. developed the experiment

Press as DOI: 10.1164/rccm.202003-0658LE on April

ORCID IDs: 0000-0003-3352-8824 (Y.D.); 0000-0002-5587-0412 (X.W.); 0000-0002-4397-5217 (C.C.); 0000-0001-7770-2754 (P.Z.); 0000-0002-1475-2858 (L.T.). *These authors contributed equally to this work. ‡ These authors contributed equally to this work.x Corresponding author (e-mail: guogang_xu@163.com).

Updated American Thoracic Society/European Respiratory Society (ATS/ERS) technical standards for spirometry were recently published in the Journal (1). Some recommendations regarding calibration verification are based on expert opinion, not science. Although these recommendations would not cause any harm, they are unproven directives that clinicians will feel obligated to follow. These recommendations are easy to test, overcoming the need to rely on expert opinion. We tested two directives that we believed were particularly dubious.

"If an in-line filter is used in spirometry testing, then it must also be used during recalibrations and verifications" (1). The user is not informed as to why a filter must be used during calibration and verifications, but it is presumably related to the potential of the filter to affect flow (i.e., turbulence). However, this is not an issue for volume-based spirometers, which are still in use on some systems. We tested this theory by performing calibration verifications with 3L syringes on several different spirometer types (four pressure differential pneumotachs [two metal screens from different manufacturers; one Fleisch; one Pitot tube], one heated wire pneumotach, and one dry rolling seal volume spirometer) at low, mid, and high flows with and without a filter. The largest difference we measured was 620 ml (0.7%), well within the 2019 ATS/ERS calibration standard of 3L 6 90 ml (3%) (1). We could not find a clinically meaningful difference in calibration verification results whether a filter was used or not.

"Holding the syringe body to steady the syringe during a calibration verification can raise its temperature and contribute to measurement error" (1). The theory behind this recommendation is sound: raising the temperature of the gas that is supposed to be measured at room temperature may affect the recorded values. However, can simply holding the calibration syringe affect the temperature of the gas inside the syringe? To test this theory, calibration verification data performed on a pressure differential pneumotach while not holding the syringe was compared with values measured after the syringe was held in a bear hug for a full minute, as well as after the syringe was placed in a heated drier at 96 8 F for 10 minutes. After the bear hug, the recorded values were 120 ml (10.7%) at low flows, 0 ml at mid flows, and 110 ml (10.3%) at high flows. After calibration syringe exposure to 96 8 F for 10 minutes, the recorded values were 130 ml (11%) at low flows, 0 ml at mid flows, and 110 ml (10.3%) at high flows. On the basis of this comparison, holding the syringe during spirometer calibration does not appear to have a significant impact on recorded values. The ATS/ERS recommendations that filters should be used and the syringe not be held during spirometer calibration and verification may not be necessary. n