key: cord-0909928-hj1g71ig
authors: Liu, Dong; Yang, Qingyuan; Chen, Wei; Chen, Hong; Feng, Yun; Hu, Weiping; Xie, Yusang; Lin, Huihuang; Yan, Jiayang; Qu, Jieming
title: Troponin I, a risk factor indicating more severe pneumonia among patients with novel coronavirus infected pneumonia
date: 2020-07-02
journal: Clin Infect Pract
DOI: 10.1016/j.clinpr.2020.100037
sha: 955a4f4f071e53a21a6d580759479f518f750af3
doc_id: 909928
cord_uid: hj1g71ig

BACKGROUND: In December 2019, a novel communicable disease, novel coronavirus infected pneumonia (NCIP) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) broke out. We aimed to analyze the characteristics and severity of patients with myocardial damage in NCIP. METHODS: We enrolled 215 adult patients with NCIP from January 2020 to February 2020. Outcomes were followed up until March 1st, 2020. RESULTS: 28.37% of the total patients showed increased level of TnI (> 0.040 ng/ml). Patients were older and had more cardiovascular complications in increased TnI group. Higher CRP, NT-proBNP, lower immune CD3, CD4 and CD8 cell account and more involved lobes detected by CT scan in the lung were observed in increased TnI group. Patients with elevated TnI had higher CRUB-65 scores and were more likely given glucocorticoid therapy and mechanical ventilation than patients in normal TnI group. CONCLUSIONS: Markers of cardiomyocyte injury were elevated not least in elderly males with pre-existing cardiovascular disease. Patients with elevated TnI presented more severe situation, leading to multiple organ dysfunctions, which appeared as a pivotal feature of patients with NCIP that requires attention by clinicians in order to provide necessary treatment as soon as possible and improve patients' outcomes.

In December 2019, a novel coronavirus infected pneumonia (NCIP), originating from the Huanan Seafood Market in Wuhan broke out. Being highly transmissible through mainly air droplets and contact, this epidemic has spread throughout the globe and has caused a total of over 1500000 infections outside China as of April 10, 2020. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for this infection was soon isolated and sequenced by Chinese Center for Disease Control and Prevention. 1 SARS-CoV-2 within the subgenus sarbecovirus, Orthocoronavirinae subfamily, turns out to be another coronavirus that infect human currently.

In The Lancet, there are two research reported the clinical characteristics of patients with SARS-CoV-2 infection. 2,3 Symptoms, CT features, treatment, mortality, and comparison between ICU patients and non-ICU patients were reported. 4

Aside from pulmonary edema and hyaline membrane formation observed in lung, the biopsy samples taken from heart tissue from a severe case of NCIP showed a few interstitial mononuclear inflammatory infiltrates and indicated myocardial damage. 5 We also observed elevated myocardial enzymes in severe patients with NCIP. Therefore, we retrospectively analyzed the characteristics and severity of patients with myocardial damage in NCIP.

J o u r n a l P r e -p r o o f 3. Severe type: if one of the following conditions was met:

(1) Respiratory distress, RR ≥ 30 per min;

(2) Finger oxygen saturation (SaO2) ≤ 93% in resting state;

(3) Partial pressure of arterial oxygen (PaO2) / concentration of oxygen inhaled (FiO2) ≤ 300mmHg.

J o u r n a l P r e -p r o o f 4. Critical type: if one of the following conditions was met:

(1) Respiratory failure occurs and mechanical ventilation is needed;

(2) Shock occurs;

(3) Patients with other organ dysfunction need intensive care unit (ICU) monitoring treatment.

Patients with incomplete data were excluded from this study.

We collected demographic data, symptoms, laboratory, radiological characteristics, severity, and treatment from patients' electronic medical records. Two physicians reviewed the date collected to double check.

In this study, patients (n=215) involved were divided into two groups: normal TnI group (n=154) and increased TnI group (n=61) according to their level of troponin I (TnI) at admission. The above collected characteristics were compared between the two groups.

J o u r n a l P r e -p r o o f age and sex. All tests were two-sided and a p <0.05 denoted statistical significance. P value and the one adjusted by age and sex were listed in Tables. All analyses were done by SPSS (version 26.0).

The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

This was a retrospective case series study and no patients were involved in the study design, setting the research questions, or the outcome measures directly. No patients were asked to advise on interpretation or writing up of results.

Totally, there are 222 patients admitted in the hospital. Seven patients lack the measurement of TnI. Therefore these 7 patients were excluded from this study. The participation rate is 96.85%. The patients were divided into two groups as normal TnI group (0～0.040 ng/ml, n=154) and increased TnI group (>0.040 ng/ml, n=61) according to their TnI level on admission. The majority patients were men (53%).

Patients in normal TnI group were about 13 years younger than those in increased TnI J o u r n a l P r e -p r o o f group (p=0.001) ( Table 1) . 80% or so of study population alleged exposure history (Table 1) . More patients had the complications of hypertension and coronary heart disease in increased TnI group than in normal TnI group (16.2% vs. 41.0% respectively; p<0.001; 7.1% vs. 16.4%; p=0.039) ( Table 1) .

Cases in increased TnI group had higher score of CURB-65 at admission than patients in normal TnI group (p<0.001). Most patients had fever or cough (80.5% and 48.8%).

The distribution of symptoms was similar between these two groups (Table 1) .

On admission, level of CRP, direct bilirubin, creatinine, myoglobin, NT-proBNP, procalcitonin and fibrinogen were higher in increased TnI group than those in normal TnI group (Table2). Compared with normal TnI group, the patients with lymphocyte count less than 1*10 9 /L and D-dimer more than 0.5 μg/L was more in increased TnI group (37.0% vs. 54.1%, 31.2% vs. 50.8% in normal TnI group and increased TnI group respectively; p=0.022, p=0.007) ( Table 2) . Arterial blood gas between the two groups showed no significant differences. Compared with cases in increased TnI group, patients in normal TnI group presented higher level in CD3 count, CD4 count and CD8 count than those in increased TnI group, while their level of antibodies (IgG, IgA, IgM) were similar (Table 2 ).

In the terms of CT examination, ground-glass opacities (94.9%) and pleural thickening (59.1%) were the most common manifestations (Table 3) . Images suggested more patients with 4-5 lobes involved in increased TnI group (52.00% vs.

J o u r n a l P r e -p r o o f 75.4% in normal TnI group and increased TnI group respectively; p=0.006) (Table 3) .

The proportion of severe and critical illness in increased TnI group was significantly higher than those in normal TnI group (11.9% vs. 14.8%, 2.8% vs. 11.5% in normal TnI group and increased TnI group respectively; p=0.021) ( Table 4) . Regarding therapy situation, subjects in increased TnI group were more likely given glucocorticoid therapy and mechanical ventilation than patients in normal TnI group (Table 4) .

Coronavirus could result in severe respiratory syndrome 6 However, myocardial lesions and the elevation of myocardial enzymes in coronavirus infections are limited.

Our study found that SARS-CoV-2 induced elevated myocardial enzymes and myocardial injury. From the present study, 28.37% of the total patients showed increased level of TnI. Elevated TnI usually indicates myocardial damage. Previous study reported increased serum troponin concentration might be a biomarker to stratify risk in subjects with pneumonia. 7 Troponin elevation in sufferers with COVID-19 is likely to be due to multifactorial non-ischemic causes, and less likely to be on account of atherothrombotic coronary occlusion. 8 Biopsy heart specimens of a patient with SARS-CoV-2 showed a few interstitial mononuclear inflammatory infiltrates. 5 SARS-CoV-2 was reported to use the same same cell entry receptor as J o u r n a l P r e -p r o o f SARS-CoV (human angiotensin-converting enzyme 2 [hACE2]). 9 As a homologue of the key enzyme of renin-angiotensin system, ACE2 is highly expressed in arterial and venous endothelial cells and arterial smooth muscle cells aside from lungs, which account for myocardium's susceptibility of SARS-CoV-2. 10-12 Previous study suggested SARS-CoV mediated myocardial inflammation and damage through down-regulating myocardial ACE2 system, which might serve as the mechanism of SARS-CoV-2 impairing heart as well. 13

On the one hand novel coronavirus directly invades the myocardium and results in myocardial damage. On the other hand, previous cardiovascular complications aggravate this process. Pneumonia and cardiac disease frequently coexist in the same patients. 14 New-onset or worsening cardiac complications, not least atrial fibrillation are well-characterized complications of acute pneumonia. 15 Researchers have showed during the course of community-acquired pneumonia, a high incidence of cardiac complications, was independently associated with increased short-term mortality. 7 Consistent with previous study, 2,16 the comparison of baseline characteristics indicated elderly male with comorbidities including hypertension and coronary heart disease were more likely to present a high level of TnI. A prospective study of elderly persons reported pre-existing heart failure figures as a risk factor for the development of pneumonia and as well increased the risk of pneumonia-related death. 17 This phenomenon suggests that patients with underlying cardiovascular disease have less robust cardiac reserve function, therefore their cardiac systolic and diastolic J o u r n a l P r e -p r o o f dysfunction are more vulnerable when virus attacks the myocardium. Hypoxia caused by pneumonia leads to an increase in heart rate, which induces the shortening diastolic time and insufficient coronary perfusion, thereby aggravating myocardial ischemia and hypoxia, ultimately causing instability and even collapse of the circulatory system.

In our research, that patients with elevated myocardial enzymes had higher CRUB-65 scores and higher NT-proBNP-a biomarker of cardiac function confirm the above theory from another aspect.

With regard to laboratory tests and CT scan results, higher CRP, lower immune CD3, CD4 and CD8 cell account and more involved lobes in the lung were observed in increased TnI group indicating higher virus load and more severe inflammatory response, also known as cytokine storm, a phenomenon associated with a wide variety of infectious and noninfectious diseases. 18 The storm of inflammatory factors can further cause disorders in multiple organs and systems as patients in increased TnI group showed elevating bilirubin, creatinine and D-dimer. Creatinine is the product of muscle metabolism in the human body and is mainly excreted by the glomerular filtration. Increased creatinine concentration indicates kidney damage. As a specific degradation product of fibrin, D-dimer increase when hypercoagulability and secondary fibrinolysis take place in the body. Figuring as a biomarker of liver function, bilirubin elevates if liver damage happens. Aforementioned multiple organ disorders along with myocardial damage exacerbated patients' condition.

Our study suffers from three limitations: 1. As a cross-sectional study, we have not J o u r n a l P r e -p r o o f included data of dynamic changes in myocardial enzymes, echocardiography and not evaluated diastolic function and ejection fraction of heart. The relationship between heart damage and NCIP pneumonia could be better assessed if aforementioned data could be included. 2. The data in this study was from 2 centers and incomplete data has been excluded, possibly resulting in a certain degree of selection bias. 3. For part of patients were still hospitalized as of press, we failed to know their eventual prognosis. Nevertheless, this retrospective study suggested myocardial damage is not ought to be ignored in the diagnosis and treatment of patients with NCIP.

Myocardial enzymes were elevated in a significant proportion of patients with NCIP, not least in elderly males with pre-existing cardiovascular disease. Patients with elevated myocardial enzymes presented a stronger immune and inflammatory response, leading to multiple organ dysfunctions including heart, liver and kidney which appeared as a pivotal feature of patients with NCIP that requires attention by clinicians in order to provide necessary treatment as soon as possible and improve patients' outcomes. a, other diseases referred to other organ diseases except for the above diseases.

J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f 

Trends in hospitalizations for pneumonia among persons aged 65 years or older in the United States

Cardiac complications in patients with community-acquired pneumonia: a systematic review and meta-analysis of observational studies

Association of Cardiac Injury with Mortality in Hospitalized Patients with COVID-19 in

P-values between two groups were calculated by Fisher's exact test, or Chi-square test. Adjusted P-values were calculated by covariance analysis after adjusting age, sex