Association between NT-proBNP Level and the Severity of COVID-19 Pneumonia

In this study, we investigated the association between the plasma NT-proBNP level at admission and the severity of COVID-19 pneumonia. For this retrospective, single-centre cohort study, we enrolled consecutive patients from February 9 to March 4, 2020, in a COVID-19 ward of Hubei General Hospital (East Branch) in Wuhan, which is a government-assigned centre for COVID-19 treatment. Diagnosis was confirmed by microbiological and radiographic findings following the interim guidance of the World Health Organization (WHO). A total of 91 (92.9%) patients were finally included in this study. The median age of the patients was 61 years (IQR, 47–69), and 39 (43.0%) of them were male. Two cases of death were reported (2.3%). Twenty-three patients (25.3%) had NT-proBNP levels above 300 pg/ml. Higher NT-proBNP levels were associated with worse PSI and CT scores. The natural logarithm of the NT-proBNP level was positively correlated with the PSI and CT scores (PSI score: rS = 0.396, P=0.001; CT score: rS = 0.440, P < 0.001). Patients with NT-proBNP ≥300 pg/ml showed a potential risk for higher mortality than patients with NT-proBNP <300 pg/ml (mortality rate, 8.7% vs. 0%; P=0.062). The plasma NT-proBNP level of COVID-19 patients was significantly related to the severity of pneumonia.


Introduction
Recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly and has attracted attention given the gravity of the situation. Since the outbreak of coronavirus disease 2019 (COVID-19), cardiovascular complications have become an important cause of deterioration and death in many patients [1,2]. Cardiovascular complications of acute pneumonia, including myocarditis and exacerbation of cardiac insufficiency, have been well recognized during previous historical epidemics [3]. An increase in the level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) indicates impairment of cardiac function and is an important biomarker for the diagnosis and estimation of prognosis in cardiac insufficiency. In the current study, we aimed to investigate the association between the plasma NT-proBNP level at admission and the severity of COVID-19 pneumonia.

Study Population.
For this retrospective, single-centre cohort study, we enrolled consecutive patients from February 9 to March 4, 2020, at a COVID-19 ward (with a medical assistance team from West China Hospital) in Hubei General Hospital (East Branch) in Wuhan, China, which was assigned by the government and was responsible for the treatment of patients with COVID-19. COVID-19 pneumonia was diagnosed based on the interim guidance of the World Health Organization (WHO) [4]. Laboratoryconfirmed cases were defined by a positive result on a realtime reverse-transcriptase polymerase chain reaction (RT-PCR) assay of nasal and/or pharyngeal swabs. Only cases confirmed by microbiological and radiographic findings were eligible for inclusion. We excluded patients with chronic heart failure, severe chronic kidney disease (eGFR <30 ml/min/1.73 m 2 ), or those who did not have NT-proBNP results at admission (the flowchart of patient inclusion is presented in Figure 1). Demographic data, medical history, vital signs at admission, laboratory tests, and radiographic results were obtained from the patients' electronic medical records and reviewed by two independent researchers.

PSI.
We used the pneumonia severity index (PSI) to quantify disease severity [5]. Briefly, patients who met the following criteria were defined as class I: (1) age ≤50; (2) no history of any of the following coexisting conditions: neoplastic disease, congestive heart failure, cerebrovascular disease, renal disease, or liver disease; and (3) none of the following abnormalities on physical examination: altered mental status, pulse ≥125/minute, respiratory rate ≥30/minute, systolic blood pressure <90 mmHg, or temperature <35°C or ≥40°C. e other patients were assigned to risk classes II-V according to their clinical characteristics (the flowchart for the pneumonia severity index is provided in Supplementary Appendix I, Figure S1).

CT Score.
Attending physicians in respiratory medicine reviewed the high-resolution chest computed tomography (CT) images to compute the CT scores, which were used to quantify the overall lung involvement [6]. Briefly, thinsection CT imaging scans were reviewed by attending physicians in respiratory medicine. Ground-glass opacities (GGOs) were defined as hazy areas of increased opacity or attenuation without concealing the underlying vessels. Consolidation was defined as homogeneous opacification of the parenchyma with obscuration of the underlying vessels. e presence of parenchymal bands, irregular linear opacities, interfaces, and traction bronchiectasis was considered evidence of probable fibrosis. e extent of involvement was also evaluated. Each lung was divided into three zones: upper (above the carina), middle (below the carina up to the inferior pulmonary vein), and lower (below the inferior pulmonary vein) zones. Each lung zone (total of six lung zones) was assigned a score that was based on the following: score 0, 0% involvement; score 1, less than 25% involvement; score 2, 25% to less than 50% involvement; score 3, 50% to less than 75% involvement; and score 4, 75% or greater involvement. e summation of scores provided the overall lung involvement score (maximal CT score for both lungs was 24).

Adverse Clinical Events.
Composite events included death and requirements of extracorporeal membrane oxygenation (ECMO), mechanical ventilation, and high-flow nasal cannula (HFNC) oxygen therapy. e mechanical ventilation requirement included noninvasive ventilation and incubated/tracheotomy ventilation.

Ethics Approval.
is report was approved by the West China Hospital Ethics Committee (2020-226). Oral informed consent was obtained from patients, and written   informed consent was waived by the Ethics Committee for emerging infectious diseases.

Statistical
Analysis. Data are expressed as the median and interquartile range (IQR (25th to 75th percentiles)) for continuous variables due to the skewed distribution (tested by the Shapiro-Wilk normality test) and as the count and percentage for categorical variables. e baseline demographics and clinical characteristics were compared between patients according to the plasma NT-proBNP levels at admission (<300 pg/ml or ≥300 pg/ml) using the Kruskal-Wallis test or the chi-squared test, as appropriate. A plasma NT-proBNP level <300 pg/ml was chosen as the cutoff value previously recommended for acute heart failure diagnosis [7]. e differences in NT-proBNP levels among   PSI risk classes and CT score tertiles were tested using the Kruskal-Wallis test. Spearman's correlation coefficient was used to measure the association of the natural logarithm of NT-proBNP with the PSI and CTscores. Receiving operating characteristic (ROC) analysis was used to compare the predictive value of hs-cTnI, NT-proBNP, or the combination of these two biomarkers for the composite endpoint. cTnI and NT-proBNP entered the models as categorical variables but not as continuous variables. e cutoff point for cTnI was the 99th percentile upper reference limit (0.05 ng/ml), and that for NT-proBNP was 300 pg/ml. All statistical analyses were performed with IBM SPSS Statistics software (version 26.0) and Stata/SE software (version 15.1).

Clinical Characteristics.
A total of 91 (92.9%) patients were finally included in this study. e clinical characteristics of the patients are presented in Table 1. e median age of patients was 61 years (IQR, 47-69), and 39 (43.0%) of them were male. Hypertension was the most common coexisting illness (20.9%), and 10 patients (11.1%) had hs-cTnI values above the 99th percentile upper reference limit, which indicated acute myocardial injury. Twenty-three patients (25.3%) had NT-proBNP levels ≥300 pg/ml. White blood cell counts, plasma D-dimer levels, C-reactive protein levels, and hs-cTnI levels were higher in patients with NT-proBNP ≥300 pg/ml than in patients with NT-proBNP levels <300 pg/ml. e median NT-proBNP level at admission was 91.2 pg/ml (IQR, 30.0-305.4).

Clinical Outcomes.
In total of 91 hospitalized patients, 2 cases of death (mortality rate: 2.3%) and 10 cases with composite events (events rate: 11.0%) were reported. Patients with NT-proBNP levels ≥300 pg/ml showed a potential risk for higher mortality (8.7% vs. 0%, p � 0.062) and more composite events (21.7% vs. 7.4%, p � 0.115) than patients with NT-proBNP levels <300 pg/ml (Table 2). e combination of cTnI and NT-proBNP seemed to show superior predictive value for the composite events compared

Discussion
is study found that the plasma NT-proBNP level of COVID-19 patients was related to the severity of pneumonia. Patients with higher plasma NT-proBNP levels showed a potential trend for a higher risk of adverse clinical events. e combination of cTnI and NT-proBNP seemed to show superior predictive value for the composite events compared with each individual component. e cardiovascular complications caused by coronavirus pneumonia outbreaks have previously highlighted the seriousness of this issue. In the 2003 SARS (severe acute respiratory syndrome) epidemic, researchers found that infected patients had complications such as hypotension, arrhythmia, diastolic dysfunction, and cardiac remodeling [8]. Pan et al. found that patients with severe SARS infection may experience cardiac arrest and even death [9]. Li et al. reported that echocardiography frequently demonstrates subclinical left ventricular diastolic impairment in SARS patients [10]. In the later MERS (Middle East respiratory syndrome) epidemic, some patients with this infection also had acute myocarditis and acute HF [11]. A recent study showed that 5 of 41 COVID-19 patients (12%) were diagnosed with a virus-related cardiac injury, which mainly manifested as a substantial increase in hypersensitive troponin I (hs-cTnI) (>28 pg/mL) [12]. Another study reported that, among 138 COVID-19 patients, 16.7% had arrhythmias and 7.2% had acute myocardial injury [2]. In this study, there  were twice as many patients with NT-proBNP levels ≥300 pg/ml as there were patients with abnormal hs-cTnI values. is result indicated that cardiac dysfunction may be more common than cardiac injury in COVID-19 patients. A previous study reported that more than one-third of patients with pneumonia had transient left ventricular dysfunction, even in patients without a history of cardiac disease [3]. Elevated levels of interleukin (IL)-1β, IL-6, IL-12, interferoninducible protein-10 (IP-10), and monocyte chemotactic protein-1 (MCP-1) can be found in some COVID-19 patients, which may be due to the systemic inflammatory storm resulting from an overaggressive host immune response to viral infection [12]. Cardiac dysfunction may be masked by pneumonia symptoms, which may delay treatment. Plasma concentrations of B-type natriuretic peptides increase during the acute phase of pneumonia, and the magnitude of this increase is associated with the severity and outcome of the infection [13]. Recently, Huang et al. reported that COVID-19 patients with cardiac injury always had higher BNP levels and higher hospital mortality than non-COVID-19 patients [14].
us, in severe cases of COVID-19, the measurement of NT-proBNP levels and the early monitoring of the possibility of HF may be helpful in the prevention and treatment of cardiac complications. Furthermore, our study revealed that increased concentrations of NT-proBNP in COVID-19 patients are more likely to result in worse clinical events.
Some limitations existed in the current study. First, this study is based on small sample size and a single-centre design, and bias would influence the results. Second, because of the limitations of medical resources at the onset of COVID-19, some patients lack electrocardiography data or echocardiography data, which limits the determination of the features and potential mechanisms of heart failure.
ird, because the clinical observations of patients are still ongoing, many patients with and without cardiac dysfunction have not reached clinical endpoints. Further studies with larger population size and in multiple centres are warranted to investigate this issue in COVID-19 patients.

Conclusion
is study found that the plasma NT-proBNP level of COVID-19 patients was significantly related to the severity of pneumonia, indicating that HF needs to be assessed in this disease. e plasma test of NT-proBNP should be performed in COVID-19 patients to screen for heart dysfunction. is finding may help us identify COVID-19 pneumonia patients with coexisting HF, allowing for the implementation of earlier management strategies.

Data Availability
e data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest
e authors declare that there are no conflicts of interest in this work.

Authors' Contributions
Lan Wang, Fei Chen, and Lin Bai authors contributed equally to this work.