Clinical features and outcomes of 2019 novel coronavirus-infected patients with high plasma BNP levels

The authors had full access to all of the data in the study and take 18 responsibility for the integrity of the data and the accuracy of the data analysis. All authors 19 have no conflict of interest to declare. 20 21 22 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 2, 2020. ; https://doi.org/10.1101/2020.03.31.20047142doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

23 Aims 24 To explore clinical features and outcome of 2019 novel coronavirus(2019-nCoV)-infected 25 patients with high BNP levels 26

and results 27 Data were collected from patients’ medical records, and we defined high BNP according to 28 the plasma BNP was above > 100 pg/mL. In total,34 patients with corona virus disease 29 2019(COVID-19)were included in the analysis. Ten patients had high plasma BNP level. The 30 median age for these patients was 60.5 years （ interquartile range, 40-80y） , and 6/10 (60%) 31 were men. Underlying comorbidities in some patients were coronary heart disease (n=2, 32 20%) ， hypertesion （ n=3， 30%） , heart failure (n=1,10%)and diabetes (n=2, 20%). Six (60%) 33 patients had a history of Wuhan exposure. The most common symptoms at illness onset in 34 patients were fever (n=7, 70%), cough (n=3, 30%), headache or fatigue （ n=4,40%） . These 35 patients had higher aspartate aminotransferase(AST), troponin I, C reactive protein and lower 36 hemoglobin, and platelet count,compared with patients with normal BNP, respectively. 37 Compared with patients with normal BNP, patients with high BNP were more likely to 38 develop severe pneumonia, and receive tracheal cannula, invasive mechanical ventilation, 39 continuous renal replacement therapy, extracorporeal membrane oxygenation, and be 40 admitted to the intensive care unit. One patient with high BNP died during the study. 41

42 High BNP is a common condition among patients infected with 2019-nCoV. Patients with 43 high BNP showed poor clinical outcomes 44 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 2, 2020. ; https://doi.org/10.1101/2020.03.31.20047142doi: medRxiv preprint

coronavirus, high BNP levels, clinical features,outcomes 45

46 The 2019 novel coronavirus (2019-nCoV), a new fatal virus that emerged at the end of 2019, 47 is a growing public health concern worldwide (1). The findings from previous studies show 48 that some infected patients had abnormal laboratory test results, including blood cell counts , 49 BNPand brain natriuretic peptide(BNP) and so on (2) (3). However, as a new coronavirus, we 50 still know little about whether 2019-nCoV is more likely to be harmful for these patients with 51 with high plasma BNP levels and the role of BNP in corona virus disease 2019(COVID-19). 52 More detailed investigations of the relationship between BNP and the clinical outcomes of 53 people infected with 2019-nCoV are urgly needed. 54 Brain natriuretic peptide (BNP), a member of a family of natriuretic peptides ,was first 55 idendified in 1988 and discovered to be present in high concentrations in cardiac 56 tissues, , especially the ventricles (4). Initial studies showed that BNP levels were strongl 57 related to impaired left ventricular (LV) function (5). In recent years, BNP, as a valuable 58 clinical biochemical marker, has been widely used in the diagnosis, prognosis and therapeutic 59 effect evaluation of cardiovascular diseases such as acute coronary syndrome, right 60 ventricular dysfunction,pulmonary disease, diastolic dysfunction (6).However, plasma BNP 61 levels are affected by many factors. BNP is not only regulated by myocardial extension, but 62 also affected by factors such as tachycardia, epinephrine, thyroxine, vasoactive peptide and 63 infection and so on (7) . 2019-nCoV , as a new virus, although it mainly damages lung tissue, 64 some studies have found that it also has a destructive effect on the heart. A recent study 65 indicate N-Terminal pro-brain natriuretic peptide(NT-proBNP) has a prognostic value in 66 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 2, 2020. ; https://doi.org/10.1101/2020.03.31.20047142doi: medRxiv preprint severe covid-19 patients (8).However, The role of BNP in COVID-19 patient is still 67 unknown.. 68 This paper provides an overview of the clinical features of 2019-nCoV-infected patients 69 with high plasma BNP levels to provide insight into the prevention and treatment for these 70 patients. 71 72

73 In total,34 patients with corona virus disease 2019(COVID-19)were included in analysis. 74 Patients were admitted to Guangzhou eighth people’s hospital from January 20, 2020, to 75 February 24, 2020. Throat swab specimens were gathered from all patients after admission, 76 and Real-Time polymerase chain reaction were performed to detect 2019-nCoV ribonucleic 77 acid .All patients with COVID-19 were diagnosed based on the World Health Organization 78 interim guidelines(9). Unless otherwise specified, all values are the first data after admission, 79 and if the index was measured more than twice, we chose the highest value for analysis. High 80 BNP level was diagnosed if the plasma BNP were above the 99th percentile of the upper 81

limit (> 100 pg/mL)) using the tridge BNP test (Beckman Coulter Inc., Brea, CA, 82 USA). Pneumonia severity was defined according to the international guidelines for 83 community-acquired pneumonia(10). The epidemiological, laboratory, clinical and outcome 84 data are derived from the patient's electronic medical records. the ethics commissions of the 85 Guangzhou Eighth people’s hospital has approved this study , with a waiver of informed 86 consent. 87 Continuous variables were expressed as mean ± standard deviation for normally 88 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 2, 2020. ; https://doi.org/10.1101/2020.03.31.20047142doi: medRxiv preprint distributed data or as median (interquartile range,IQR) for skewed distributions. Frequency 89 data were presented as proportions. Student’s t test or the Mann–Whitney U test were 90 performed for continuous variables when appropriate, whereas differences in categorical 91 variables were assessed using the Chi-square test or Fisher’s exact test. SPSS 25.0 (IBM Corp. 92 Armonk, NY , USA) were used to perform All analyses and a two-tailed p-value < 0.05 was 93 considered statistically significant. 94 95

96 1. Epidemiological features of 2019-nCoV- infected patients with high BNP levels. 97 A total of 34 patients were included and divided into two groups (high BNP group and 98 normal group) in the final analysis. Ten patients had high plasma BNP level (>100pg/mL). 99 The median age for these patients was 60.5 years （ interquartile range, 40-80y ） , and 6/10 100 (60%) were men. Underlying comorbidities in some patients were coronary heart disease 101 (n=2, 20%) ， hypertesion （ n=3， 30%） , heart failure (n=1,10%)and diabetes (n=2, 20%). Six 102 (60%) patients had a history of wuhan exposure. The epidemiological characteristics of the 103 study participants are presented in Table 1. 104 105 2. Clinical features and laboratory findings of 2019-nCoV-infected patients with high 106 BNP levels 107 The most common symptoms at illness onset in patients were fever (n=7, 70%), cough (n=3, 108 30%), headache or fatigue （ n=4,40% ） . These patients had higher aspartate amino 109 transferase(AST),troponin I,C reactive protein and lower hemoglobin,and platelet 110 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 2, 2020. ; https://doi.org/10.1101/2020.03.31.20047142doi: medRxiv preprint count,compared with patients with normal BNP, respectively. The clinical features and 111 selected laboratory findings of the study participants are presented in Table 2. 112 3.Treatments and outcomes of 2019-nCoV-infected patients with high BNP levels 113 Compared with patients with normal BNP, patients with high BNP were more likely to 114 develop severe pneumonia (80% vs 8.3%), and receive tracheal cannula(70% vs 0%), 115 invasive mechanical ventilation (40% vs 4.2%), continuous renal replacement therapy(40% 116 vs 0%), extracorporeal membrane oxygenation(30% vs 0%), and be admitted to the intensive 117 care unit (90% vs 8.3%). One patient with high BNP died during the study.The 118 epidemiological characteristics and outcomes of the study participants are presented in Table. 119 120

121 To the best of our knowledge, this is the first study systematically exploring clinical features 122 and outcomes of 2019 novel coronavirus-infected patients with high BNP(not NT-proBNP) 123 levels. Our results showed that 2019-nCoV infected patients with high plasma BNP levels 124 had worse clinical outcomes compared with patients with normal plasma BNP levels. 125 BNP and NT-proBNP, peptides produced by cardiomyocytes are widely used to guide 126 in diagnosis, prognosis and treatment of heart failure (11). It is well known that the level of 127 BNP in plasma is affected by many factors, such as inflammation and stress reaction and so 128 on (12).Therefore, it is very common for patients with other disease 129 are often accompanied with high plasma BNP level. Some studies have shown patients with 130 COVID-19 often had abnormal BNP/NT-proBNP in plasma (2) (3).Howerver,by now,there is 131 no detailed investigation on clinical features and outcomes of 2019 novel 132 coronavirus-infected patients with high BNP levels.This study provides information on the 133 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 2, 2020. ; https://doi.org/10.1101/2020.03.31.20047142doi: medRxiv preprint epidemiology and outcomes of 2019-nCoV-infected patients with high plasma BNP levels. 134 Most of patients with high BNP levels in our study were usually older and often had 135 pre-existing heart disease. High BNP level following 2019-nCoV infection is associated with 136 poor patient outcomes. These patients were more likely receive mechanical ventilation, 137 tracheal cannula, continuous renal replacement therapy, extracorporeal membrane 138 oxygenation and be admitted to the intensive care unit. 139 However, the reason why the outcomes of patients with high BNP were worse is unclear. 140 Inflammation and stress can stimulate BNP production and secretion from 141 cardiomyocytes(12).The level of BNP in plasma may reflect the severity of inflammation 142 and stress. This may partly explain why patients with high plasma BNP levels had a bad 143 outcomes. This study is limited by a relatively small number of samples from patients with 144 high BNP.These data contribute information to understanding clinical manifestations and 145 outcomes of 2019-nCoV infected patients. 146 147

148 1. https://www.who.int . accessed March 15, 2020. 149 2. Lei Gao DJ, Xuesong Wen, Xiaocheng Cheng, Min Sun, Bin He. Prognostic value of 150 NT-proBNP in patients with severe COVID-19. medRxiv preprint 2020. 151 3. Peng YD, Meng K, Guan HQ, Leng L, Zhu RR, Wang BY , He MA, Cheng LX, Huang K, 152 Zeng QT. [Clinical characteristics and outcomes of 112 cardiovascular disease patients 153 infected by 2019-nCoV]. Zhonghua xin xue guan bing za zhi. 2020 Mar 2;48(0):E004. 154 4. Wilkins MR, Redondo J, Brown LA. The natriuretic-peptide family. Lancet. 1997 May 155 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 2, 2020. ; https://doi.org/10.1101/2020.03.31.20047142doi: medRxiv preprint 3;349(9061):1307-1310. 156 5. 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Prognostic value of 169 NT-proBNP in patients with severe COVID-19. medRxiv 2020030720031575; . 170 2020.03.07.20031575. 171 9. WHO. Clinical management of severe acute respiratory infection when Novel 172 coronavirus (nCoV) infection is suspected: interim guidance. 173 https://wwwwhoint/publications-detail/clinical-management-of-severe-acute-respiratory-infe174 ction-whennovel-coronavirus-(ncov)-infection-is-suspected. 2020. 175 10. Ranieri VM RG, Thompson BT, et al;. ARDS Definition Task Force. Acute respiratory 176 distress syndrome: the Berlin definition. Jama. 2012;307()(23). 177 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 2, 2020. ; https://doi.org/10.1101/2020.03.31.20047142doi: medRxiv preprint 11. V olpe M, Battistoni A, Rubattu S. Natriuretic peptides in heart failure: Current 178 achievements and future perspectives. International journal of cardiology . 2019 Apr 179 15;281:186-189. 180 12. Matsuo A, Nagai-Okatani C, Nishigori M, Kangawa K, Minamino N. Natriuretic 181 peptides in human heart: Novel insight into their molecular forms, functions, and diagnostic 182 use. Peptides. 2019 Jan;111:3-17. 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 2, 2020. ; https://doi.org/10.1101/2020.03.31.20047142doi: medRxiv preprint 200 Table 1. The epidemiological features of 2019-nCoV-infected patients with 201 high BNP levels 202 Variables BNP>100 (N=10) BNP ≤ 100 (N=24) P Age (Y) 60.5(40-80) 38(33-52) 0.02* Male, No(%) 6（ 60） 12（ 50） 0.72 Exposure history in Wuhan, No(%) 6（ 60） 6(25) 0.11 Diabetes, No(%) 2（ 20） 2(8.3) 0.56 Coronary heart disease, No(%) 2(20) 3(12.5) 0.62 Heart failure, No(%) 1(10) 0(0) 0.29 Arrhythmia, No(%) 1(10) 0(0) 0.29 203 204 205 206 207 208 209 210 211 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 2, 2020. ; https://doi.org/10.1101/2020.03.31.20047142doi: medRxiv preprint 212 Table2.The clinical features and selected laboratory findings of 2019-nCoV-infected 213 patients with high BNP levels 214 Variables Normal range BNP>100 (N=10) BNP ≤ 100 (N=24) P Cough, No(%) - 3(30) 15(62.5) 0.13 Fever, No(%) - 7(70) 11(45.8) 0.27 Sore throat ,No(% - 1（ 10） 6(25) 0.64 Headache or Fatigue, No(%) - 4(40) 3(12.5) 0.16 Dyspnea, No(%) - 2(20) 5( 20.8 ) 1.0 Chest pain , No(%) - 0(0) 0(0) 1.0 Palpitation, No(%) - 0(0) 1(4.2) 1.0 Heart rate （ bpm） 55-95 83(72-98) 87.5(80-97) 0.49 Temperature (°C) 36.3-37.3 36.9(36.5-38.3) 36.5(36-37) 0.09 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 2, 2020. ; https://doi.org/10.1101/2020.03.31.20047142doi: medRxiv preprint Systolic pressure(mmHg) 90-139 134(121-145) 127(110-147) 0.38 White blood cell count (10E9/L) 4-10 5.6(5.0-10.2) 5.3(3.8-6.4) 0.45 Neutrophil count (10E9/L) 1.8-6.3 3.7(3.2-7.0) 3.1(2.1-4.3) 0.27 Lymphocytes count (10E9/L) 1.1-3.2 1.0(0.7-2.2) 1.3(1.1-1.9) 0.17 Hemoglobin, g/L 113-151 115.3±27.5 132.4±18 0.04* Platelets count (10E9/L) 100-300 155.6±57.2 226.38±47.1 0.001* C reactive protein (>10mg/L) , No(%) <10 9(90) 5( 20.8) 0.00* Troponin I, ( ug/L) <0.03 0.08(0.02-0.29) 0.005(0.001-0.01) 0.00* Creatinine, μ mol/L 59~104 63.1(43.6-137.8) 60.5(51.4-77.0) 0.809 Brain natriuretic peptide (pg/mL) <100 245.5(142.5-371.8) 18(9.8-36.3) 0.00* Aspartate aminotransferase (U/L) 13-35 24.7(18.95-37.6) 17.6(13.4-19.95) 0.02* . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 2, 2020. ; https://doi.org/10.1101/2020.03.31.20047142doi: medRxiv preprint Alanine aminotransferase (U/L) 7-40 16.3(9.8-24.8) 16.6(12.8-24.5) 0.59 Myoglobin (ug/L） 17.4-105.7 32.8(15.8-156.2) 15.1(11-20.9) 0.001* Creatine kinase (U/L) 50-310 48(34.8-83.8) 56.2(42.3-78.3) 0.86 D-dimer(mg/L) <1000 1765(667.5-6085) 990(660-1280) 0.15 Bilateral pneumonia No(%) -- 9(90) 14(58.3) 0.11 215 216 217 218 219 220 221 222 223 224 225 226 227 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 2, 2020. ; https://doi.org/10.1101/2020.03.31.20047142doi: medRxiv preprint Table 3. Treatments and outcomes of 2019-nCoV-infected patients with 228 high BNP levels 229 Variables BNP>100 (N=10) BNP ≤ 100 (N=24) P Tracheal cannula, No(%) 7(70) 0(0) 0.00* Invasive mechanical ventilation, No(%) 4(40) 1(4.2) 0.02* Vasopressor therapy, No(%) 2(20) 0(0) 0.08 CRRT, No(%) 4(40) 0(0) 0.005* ECMO, No(%) 3(30) 0(0) 0.02* Acute respiratory distress syndrome, No(%) 2(20) 0(0) 0.08 Severe pneumonia, No(%) 8(80) 2(8.3) 0.00* Admission to ICU, No(%) 9(90) 2 （ 8.3） 0.00* Death, No(%) 1(10) 0（ 0） 0.29 230 231 232 233 234 235 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 2, 2020. ; https://doi.org/10.1101/2020.03.31.20047142doi: medRxiv preprint