key: cord-300458-jeuwaj50 authors: Maisch, Bernhard; Dörr, Rolf title: COVID-19—What we know and what we need to know: There are more questions than answers date: 2020-04-23 journal: Herz DOI: 10.1007/s00059-020-04929-9 sha: doc_id: 300458 cord_uid: jeuwaj50 nan COVID-19-What we know and what we need to know: There are more questions than answers This collection of short statements from the editors of HERZ/Cardiovascular Diseases is a strong signal to the readers of our journal in critical times. With up-todate comments, this issue covers a spectrum of questions raised by cardiologists with respect to COVID-19. We are grateful to Springer/Nature that we could add the contributions on COVID-19 as a perspective from and for cardiologists free of charge to this issue of HERZ, which was planned for original contributions only. Two months before the pandemic began, one of us (BM) lectured in Wuhan at an international conference on fulminantmyocarditis. Afterthe world became aware of the COVID-19 epidemic, we invited the organizers of this symposium, Professors Dao Wang and Chen Chen, to report their first experience with the pandemic [1] . At this point in time there are more questions than answers: Although a detailed risk analysis via the simulation of a "Pandemic Virus Modi SARS" was made available by the federal government of Germany to all members of parliament in January 2013 [2] , we are astonished to hear from politicians that the corona crisis is without any blueprint. Is reading and remembering so difficult? From the epidemiologists we get on a daily basis the updated statistics of infected individuals in relation to mortality. Statistics are relevant, but we must be aware that case fatality depends on the number of infected individuals and the number of patients who did not survive despite all efforts. However, we do not know the real number of asymptomatic yet infected individuals. The attempt to flatten the curves of infected and lethal cases has led to a worldwide lockdown. This has slowed down the infection rate in Germany. But we also fear that with a low herd immunity a second wave of infection might follow, since no proven antiviral treatment for COVID-19 exists and vaccination is not yet available [3] . We have learned from the virologists how SARS-CoV-2 enters host alveolar cells of the lung by using the ACE2 receptor, which needs prior activation by transmembrane protease serine 2 (TM-PRSS2). But although myocytes also express ACE2, no viral RNA was detected so far within the cardiocytes themselves. This may be due to the very limited availability of electron microscopy and the lack of in situ hybridization, which allows for exact localization. Or it may indicate nonactivation of the cardiac target cell by TMPRSS2. The immunologists and pathologists have found only a small increase of infiltrating macrophages in the few samples from tissues at necropsy. This might indicate that in the patients who died, viremia and innate immunity dominated before excessive lymphocyte infiltration occurred. Was it then truly a cytokineinduced hyperinflammation that led to multiple organ failure (MODS) or could it still be the virus? Pulmonology demonstrates with every ventilated patient that COVID-19 is a potentially lethal lung disease. But our colleagues also know that it is es-pecially the older patients with cardiac and metabolic comorbidities who are in great danger. Paradoxically, the cardiac interventionalists have reported a decrease of patients with unstable angina or STEMI, although we know that inflammation can increase plaque instability. Is it only that patients do not dare to go to the cath lab because they fear the virus? The electrophysiologists have regularly observed an increase of arrhythmias in myocarditis patients, but it is unclear whether this also holds for ventricular tachycardias in overt cardiac inflammation, which might be cytokine driven. Elective pulmonary vein isolations that were scheduled in the COVID-19 pandemic are now delayed. The severest medical challenge is to provide treatment and prevention of transmission of the virus. The generation in danger is that of the elderly, who make up one third of the German population. The first reported Chinese patient with suspected myocarditis from SARS-CoV-2 was treated with ventilation, methylprednisolone, i.v. immunoglobulins and inotropics and survived [4] . Others have treated for compassionate use 66 patients with remdesivir (Gilead), which failed for Ebola. A total of 55 authors (!) have described in an observational study with 66 COVID-19 patients without a control group a beneficial effect in the New England Journal of Medicine [5] . This is truly strange! Future randomized, placebocontrolled studies are planned such Herz as the WHO-sponsored SOLIDARITY trial. It will examine the antivirals ritonavir and lopinavir, which inhibits 3-chymotrypsin-like protease and is in use against HIV, alone or in combination with interferon-beta, remdesivir, which inhibits RNA-dependent RNA polymerase, and finally chloroquine/ hydroxychloroquine, which has been used in the prevention and treatment of malaria. It inhibits viral entry and endocytosis and may be responsible for QT-prolongation. Other approaches should also be tested in a randomized placebo-controlled fashion: IvIg, which will modulate the immune system; Tocilizumab or sarilumab, which bind the IL-6 receptor and prevent its activation and signaling; camostat mesylate, which may inhibit TMPRSS2 and thus prevent viral cell entry; and Arbidol, which targets the interaction between S protein and the ACE receptor and inhibits the membrane fusion of the viral envelope. Several teams and pharmaceutical companies worldwide are trying to develop a specific SARS-CoV-2 vaccine by either the classic approach of taking specific protein from the virus, e.g., a spike protein and performing phase 1, 2, and 3 studies to ascertain safety and efficacy. Or by using viral RNA molecules as potential vaccine. It will take at least 15 months before a safe vaccine can be introduced to the market. The use of BCG (Bacillus Calmette-Guérin), a mitigated virus used before 1998 as a tuberculosis vaccine in Germany, is enjoying an unexpected revival. It will not render immunity against COVID-19, but under the label of VPM1002 it could serve as an immunostimulant. To learn the lessons from the corona crisis we need more data from clinical studies and research. In most European countries it is still too early to exit the lockdown immediately. But we can discuss how a slow exit from the lockdown in the next 18 months might look like. We should keep in mind that COVID-19 is a worldwide pandemic. It needs worldwide solidarity and common actions. Our primary intention as physicians is to care for the health of our patients and to prevent virus transmission to doctors and staff. Or as Arthur Schopenhauer said: "Health is not everything, but everything is nothing without health. " SARS-CoV-2: a potential novel etiology of fulminant myocarditis Pharmacologic treatments for coronavirus disease 2019(Covid-19). A review Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin. Cardiovascular flashlight 2020) compassionate use of remdesivir for patients with severe Covid-19 B. Maisch and R. Dörr declare that they have no competing interests.