key: cord-0685783-6m71ubfz authors: Zhang, J.; Ding, D.; Cao, C.; Huang, X.; Fu, P.; Liang, G.; Xu, W.; Tao, Z. title: Myocardial characteristics as the prognosis for COVID-19 patients date: 2020-05-09 journal: nan DOI: 10.1101/2020.05.06.20068882 sha: 07b04f19614af7317dbb270da10243092c782cf9 doc_id: 685783 cord_uid: 6m71ubfz Background Amid the crisis of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), front-line clinicians in collaboration with backstage medical researchers analyzed clinical characteristics of COVID-19 patients and reported the prognosis using myocardial data records upon hospitalization. Methods We reported 135 cases of laboratory-confirmed COVID-19 patients admitted in The First People's Hospital of Jiangxia District in Wuhan, China. Demographic data, medical history, and laboratory parameters were taken from inpatient records and compared between patients at the Intensive Care Unit (ICU) and non-ICU isolation wards for prognosis on disease severity. In particular, survivors and non-survivors upon ICU admission were compared for prognosis on disease mortality. Results For COVID-19 patients, blood test results showed more significantly deranged values in the ICU group than those in non-ICU. Among those parameters for ICU patients, myocardial variables including troponin T, creatine kinase isoenzymes, myoglobin, were found significantly higher in non-survivors than in survivors. Conclusions Upon hospitalization abnormal myocardial metabolism in COVID-19 patients could be prognostic indicators of a worsened outcome for disease severity and mortality. On December 2019, a novel coronavirus emerged and provoked a global spreading of pneumonia diseases [1] [2] [3] [4] . The disease was later named as coronavirus disease 2019 (COVID-19) [5] . The pathogen responsible for the COVID-19 was discovered as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of April 18, 2020, over 2 million cases of COVID-19 infection were confirmed globally, constituting an unprecedented public health emergency [6] . With no effective treatment available, the mortality rate of COVID-19 has been estimated ~ 5.4% [6] . Upon inpatient admission, poor prognosis was associated with elderly age, high Sequential Organ Failure Assessment (SOFA) score, and augmented Ddimer level of COVID-19 patients [7] . Since the epidemic strike of COVID-19, respiratory and pulmonary systems have been heavily investigated to enhance understanding towards this devastating infectious disease, leaving cardiovascular parameters of patients a less explored area. Here we reported 135 laboratory-confirmed COVID-19 patients in Wuhan, China, by analyzing clinical data upon their hospital admission with a linkage to their final outcomes. Through this study by comparing clinical characteristics among non-severe, severe and deceased groups of patients, we aimed to reveal the relationship between myocardial characteristics and disease prognosis of COVID-19. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. . https://doi.org/10.1101/2020.05.06.20068882 doi: medRxiv preprint 5 The study was approved by The First People's Hospital of Jiangxia District 105 patients in non-ICU isolation ward. Written consent was waived by Ethics Commission of TFPHJD due to the emergency of a major infectious disease. All COVID-19 patients were received at TFPHJD and diagnosed by following a standard procedure [8] . The confirmed patients were treated with antiviral drugs, including oseltamivir, arbidol, and ribavirin. For the severe patients who were admitted into ICU by following the published criteria [8] , they typically developed hypoxemia, dyspnea, and even respiratory failure requiring respiratory support or invasive mechanical ventilation, and usually had complications such as liver and kidney injuries, which required blood purification. They were receiving antibiotic treatment (sulperazone, linezolid), antifungal therapy (fluconazole, caspofungin), corticosteroid therapy, respiration-assisted ventilation, All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. . https://doi.org/10.1101/2020.05.06.20068882 doi: medRxiv preprint 6 continuous renal replacement therapy. For all patients, blood cell analysis was detected by automated hematology analyzer (SYSMEX 800i, Japan), and the biochemical indicator was analyzed (Toshiba TAB2000, Japan). The biochemical markers of myocardial injury were measured (Roche Cobas 6000 Analyzer, Switzerland). Demographic data, medical history and clinical characteristics including symptoms, chest computed tomography (CT) scans, myocardial biomarkers, hematological and biochemical tests, were obtained at TFPHJD. The data access and the study were approved by Ethics Commission of TFPHJD. The categorical variables were described as frequency rates and percentages, and continuous variables were applied to describe the median and quartile range (IQR) values. Comparison of continuous variables between two groups was analyzed with unpaired Student's t test or Mann-Whitney test, as appropriate. Repeated measurements (non-normal distribution) were used following a generalized linear mixed model.  2 test was used to compare the proportion of categorical variables, and the Fisher exact test was employed when data was limited. All statistical analyses were performed using SPSS (statistical package for social sciences) version 13.0 software (SPSS Inc.). A All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. . https://doi.org/10.1101/2020.05.06.20068882 doi: medRxiv preprint 7 two-sided  of less than 0.05 was considered statistically significant unless otherwise specified. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. Admitted at TFPHJD, a total of 135 COVID-19 patients aged 17 to 89 years old were included in this study. The median age was 56.0 years (IQR 42.0-68.0), and 67 (49.6%) of them were male (Table 1) (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. . https://doi.org/10.1101/2020.05.06.20068882 doi: medRxiv preprint 9 infected those patients could develop worsened conditions. 56.7% of ICU patients had one comorbidity or more, whereas only 27.6% non-ICU patients had at least one comorbidity. We calculated the individual comorbidity percentage in ICU and non-ICU patients, and plotted them versus each other as shown in Figure 1A . Dotted diagonal (in red) indicated a hypothetically equal percentage between the two groups. As a result, hypertension stayed the farthest away from the diagonal, showing this comorbidity possibly the highest risk factor to cause COVID-19 patients on further critical condition. Following the same analysis, the other co-existing diseases, such as diabetes, bronchitis, and renal dysfunction/failure, make up probable risk factors to have negative impact on COVID-10 patients, which may aggravate the disease severity after virus infection. At the onset of COVID-19 illness, the most common symptoms appeared in 135 patients were cough (135 patients, 100%), fever (128, 94.8%), fatigue (82, 60.7%), chest pain or distress (46, 34.1%), diarrhea (32, 23.7%), vomiting (24, 17 .8%), and dyspnea (10, 7.4%) ( Table 1) . Notably, 5.2% later-confirmed positive patients experienced no fever. For patients showing dyspnea, 6 were transferred to ICU while the other 4 stayed in non-ICU isolation until fully recovered. Each symptom had a higher incidence in ICU than in non-ICU. We calculated the percentage of the above symptoms in ICU and non-ICU groups, respectively, and plotted the symptom percentage in ICU vs. that in non-ICU. As shown in Figure 1B , the diagonally dotted line indicated a hypothetically All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. . https://doi.org/10.1101/2020.05.06.20068882 doi: medRxiv preprint equal symptom percentage between two groups. This figure depicted that the later-admitted ICU patients were more likely to show initial symptoms compared with non-ICU patients, as most points that belong to ICU patients scattered above the diagonal. We performed the laboratory tests of COVID-19 patients on their first day of hospitalization, and typical parameters indicating blood, hepatic and renal function were reported ( Table 2) (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. . https://doi.org/10.1101/2020.05.06.20068882 doi: medRxiv preprint non-ICU groups. All the blood test results pointed to viral infection as well as possible bacterial co-infection. To present the prognosis between ICU and non-ICU outcomes, we plotted the percentage of each blood parameter in ICU patients vs. that in non-ICU (Figure 2A) , where the dotted diagonal line showed a hypothetically equal percentage between two groups. As most points located above the diagonal, those abnormal changes in hematological parameters indicating infection and organ damages, could serve as prognostic biomarkers for COVID-19 patients who might need further intensive care attention. We next examined biochemical markers of myocardial injury for COVID-19 patients, including troponin T (TnT), creatine kinase isoenzymes (CK), myoglobin (Mb), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) ( Table 2) patients, respectively. Among those patients, LDH content for 24 (80.0%) ICU All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. Similarly, in order to predict ICU or non-ICU outcomes, we plotted the percentage of each abnormal blood parameter in ICU patients vs. that in non-ICU patients ( Figure 2B) , where the dotted diagonal line showed a hypothetically equality between two groups. All points situated within upper diagonal area, suggesting that those abnormal increases in myocardial parameters could be meaningful to assess the prognosis for newly hospitalized COVID-19 patients. Furthermore, the higher above the diagonal line, the higher risk associated with this parameter for a more possibly critical ill case. For instance, patients with high TnT levels predicted a poorer prognosis than those with high CK levels, although both abnormal TnT and CK could serve as prognostic biomarkers for severe COVID-19 disease. Following the nucleic acid tests of SARS-CoV-2 pathogens and laboratory tests of blood samples from patients, CT scans were conducted for all patients upon hospitalization. Selected CT images were shown for non-ICU patients, and All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. . https://doi.org/10.1101/2020.05.06.20068882 doi: medRxiv preprint 13 survival and non-survival groups in ICU patients, where the extent of COVID-19 in different patients could be distinctive (Figure 3 ). In many a case, bilateral lung involvements were seen at the beginning of infection, although unilateral lung infection was not uncommon. For non-ICU patients, as shown in Figure 3A , at the lower lobe of the right lung located GGOs, together with patchy consolidation and stripy density inside. In Figure 3B Figure 3E -F finally died of respiratory failure on 15 and 24 days, respectively, after those images were taken upon hospital admission. As patients in ICU admission were more frequently showing myocardial injury compared to non-ICU patients upon hospital admission, we next investigated whether this occurrence of myocardial anomaly might foretell the eventual All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. . https://doi.org/10.1101/2020.05.06.20068882 doi: medRxiv preprint 15 patients admitted to ICU, the increased TnT level would suggest worse prognosis than the elevated CPK level, although both parameters could indicate a likely severe diseases development. This was also in line with the findings in Figure 2B , as aberrant TnT values could raise more warning signs than abnormal CPK in the course of disease severity from non-critical to critical conditions. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. . https://doi.org/10.1101/2020.05.06.20068882 doi: medRxiv preprint With 95% identity in its S gene to SARS-CoV, SARS-CoV-2 oriented its receptor-binding domain (RBD) and optimized its conformation to secure the angiotensin-converting enzyme 2 (ACE2) in the host for cell entry, showing the same manner as SARS-CoV but with higher affinity [9] [10] [11] . ACE2 was first known as a vasoconstrictive protein that regulated the renal and cardiovascular function, abundantly expressed in the pneumocytes of lung epithelia and enterocytes of small intestine [12, 13] . This may explain why in addition to the predominant respiratory or pulmonary manifestation, the gastrointestinal symptoms occurred in a substantial portion of COVID-19 patients [14] , including diarrhea or vomiting found in our study. This virus entry is further facilitated by a polybasic site containing several arginine residues in S protein of SARS-CoV-2, subject to the highly efficient cleavage of a serine protease TMPRSS2 in the target cell, which in turn drives the fusion of viral and host cellular membranes [15, 16] . In previous reports male and elderly group were found susceptible to SARS-CoV-2 [7, 17] . Our study here indicated a minimal difference between different genders of COVID-19 patients in both non-ICU and ICU groups. The fact that male could be more susceptible to COVID-19 may be associated with several non-gender factors, such as smoking history or occupational exposure to the pathogen [18] . Our research confirmed that elderliness posed a high risk of SARS-CoV-2 infection. Many have concluded this to the changing ACE2 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. . https://doi.org/10.1101/2020.05.06.20068882 doi: medRxiv preprint activity with aging, where the specific binding of ACE2 to virus outweighs the protective functions of ACE2 to major organs [19] . Our study agreed with others in that hypertension, diabetes and cardiovascular diseases made three leading comorbidities which contributed to the severity of COVID-19 [7, 17, 20] . As ACE2 plays a vital role in regulating blood pressure and renal function, chronic disease development and long-term medication may confound the ACE2 activity in each individual [21] . Meanwhile, SARS-CoV-2 infection may lead to the downregulation of ACE2 expression in a similar manner as SARS-CoV did, therefore exacerbating organ damages [22] . However, the association of COVID-19 transmissibility with ACE2 activity remains uncertain, while high frequency of those chronic diseases among population, interlinked pathogenesis between those diseases, and compromised immune systems in those patients of comorbidity, could make them vulnerable to the viral infection. COVID-19 patients were found to have higher viral load in the nasal swabs or sputum samples than in the throat swabs [23, 24] . Moreover, SARS-CoV-2 was inclined to infect the lower airway, including trachea, bronchi, and alveoli [17] . This agreed with our findings where involuntary cough was the most common symptom in COVID-19 patients, followed by febrile illness as a sign of infection. All those results pointed out that in the quest to prevent COVID-19 contraction and stop SARS-CoV-2 spreading, oronasal covering or social distancing is an imperative measure to thwart the otherwise respiratory tract All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. . https://doi.org/10.1101/2020.05.06.20068882 doi: medRxiv preprint transmission intra-or inter-personally, or it would become harder to contain the virus for avoiding further deep lung infection. Once inhalation of SARS-CoV-2 contained particles delivers virus to the lung, where alveolar epithelia actively expressed ACE2 proteins, it further induces harmful lung injuries [12] . In our study, CT images for COVID-19 patients of different disease developments pointed out pathological changes in Oronasal entry of SARS-CoV-2 led to its direct infection of pulmonary and digestive systems, as well as earning a chance to enter bloodstream and then All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. . https://doi.org/10.1101/2020.05.06.20068882 doi: medRxiv preprint 19 contract extrapulmonary organs through blood flow. Upon hospital admission, our clinical data from a substantial portion of COVID-19 patients showed the abnormality in several blood parameters, including peripheral blood cells, hepatic enzymes, renal metabolites and myocardial proteins, indicating acute assaults to immune systems together with damages to major organs including liver, kidney and heart. All parameters (except Cr and CPK) showed significant difference between ICU and non-ICU patients, establishing them as prognostic markers for status of COVID-19 severity. This result is in concert with previous reports [1, 20] . However, none of those parameters suggested a difference between survivors and non-survivors in ICU group, except myocardial markers including TnT, CK and Mb. This finding here recommended that upon hospitalization the myocardial enzyme levels could serve as prognostic indicators for in-hospital COVID-19 severity and mortality even before medical care is given. Regardless of previously underlying diseases, a considerable amount of cardiac injury in COVID-19 patients have been noticed with correlation to disease severity and mortality [29] . In our view, two pathways could be both involved, each to a different extent. Firstly, a direct viral invasion by riding the blood flow is plausible, a process mediated by ACE2 that is highly and specifically expressed in the pericytes of heart [30] . Study has revealed that SARS-CoV genome was detected in 35% autopsied heart samples of 20 SARS patients, concurrent with lowered ACE2 activity, inundated macrophages, and All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. . https://doi.org/10.1101/2020.05.06.20068882 doi: medRxiv preprint 20 significantly shortened illness durations before death [31] . This learning offers a tip for understanding SARS-CoV-2 infection. Secondly, SARS-CoV-2triggered hypercytokinemia (more well-known as cytokine storm) may result in multiorgan damages, making an indirect but deadly hit to heart [29] . As a proof, activations of both T-helper-1 (Th1) and T-helper-2 (Th2) cells were identified in COVID-19 patients, and elevated cytokine levels were found in ICU patients compared to non-ICU ones, such as interleukin-2, -7, and tumor necrosis factor . While a cascade of cytokine release was initiated, it also led to dysregulation of immune systems, promoting cardiomyocyte death and eventually heart failure. Insofar, biopsied heart sample from one COVID-19 patient did not endorse a direct cardiac impairment of SARS-CoV-2, where overactivation of Th17 and cytotoxic T cells was found in the peripheral blood, voting for an indirect heart injury [28] . More evidences are necessitated to explore the underlying mechanism of organ impairment by SARS-CoV-2, which could inspire effective treatments to decelerate and stop the increasing COVID-19 fatality. In summary, we here highlighted myocardial variables from 135 COVID-19 patients prior to their in-hospital treatment, and utilized them as prognostic indicators for disease severity and mortality of COVID-19, with a hope to assist decision-making of clinicians when treating patients. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. Table 3 . Parameters of COVID-19 ICU patients upon admission to hospital All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. Overlapping coordinates were pointed by an arrow with following descriptions. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. . https://doi.org/10.1101/2020.05.06.20068882 doi: medRxiv preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 9, 2020. . https://doi.org/10.1101/2020.05.06.20068882 doi: medRxiv preprint All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 9, 2020. . https://doi.org/10.1101/2020.05.06.20068882 doi: medRxiv preprint All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 9, 2020. . https://doi.org/10.1101/2020.05.06.20068882 doi: medRxiv preprint