key: cord-1007120-gkcnv0qr
authors: Zhu, H.; Qu, G.; Yu, H.; Huang, G.; Chen, L.; Zhang, M.; Wan, S.; Pei, B.
title: Features of α-Hydroxybutyrate Dehydrogenase during various specific periods in COVID-19 patients within Xiangyang, China: a cohort study
date: 2020-11-01
journal: nan
DOI: 10.1101/2020.10.28.20221127
sha: 94e458229adbbf30af50d3916ae6827bba602198
doc_id: 1007120
cord_uid: gkcnv0qr

Background: Coronavirus disease-2019 (COVID-19) has spread all over the world and brought extremely huge losses. There is no study to systematically analyse the features of hydroxybutyrate dehydrogenase (-HBDH) in COVID-19 patients during the periods before and after illness progression, before death and course from exposure onset. Methods: We collected all included patients' general information, clinical type, -HBDH value and outcome, and analyzed -HBDH values within different initial time and different periods. Results: In the first 30 days after symptom onset, the -HBDH median value was 156.33 U/L. The first test of -HBDH since exposure onset appeared on the 8th day, it increased from the 8th day to 18th day and decreased after the 18th day. -HBDH median value showed a slight change until it started to increase 1 day before transforming to severe type, while it continued to increase during 4 days before and after transforming to critical type. The -HBDH median value ranged from 191.11 U/L to 455.11U/L before death. Conclusions: -HBDH value increases in some COVID-19 patients, obviously in severe type, critical type and death patients, and mainly in 18 days after exposure onset and 10 days after symptom onset. -HBDH increases 1 day before transforming to severe type, continues to increase in critical type and death patients, increases rapidly 5 days before death. The increase of -HBDH suggests that COVID-19 patients have tissues and organs damage, mainly in heart. In brief, -HBDH is an important indicator to judge the severity and prognosis of COVID-19.

patients, increases rapidly 5 days before death. The increase of α-HBDH suggests that COVID-19 patients have tissues and organs damage, mainly in heart. In 23 brief, α-HBDH is an important indicator to judge the severity and prognosis of COVID-19. CC-BY-NC-ND 4.0 International license It is made available under a who has granted medRxiv a license to display the preprint in perpetuity.

is the author/funder, (which was not certified by peer review) The copyright holder for this preprint this version posted November 1, 2020. ; https://doi.org/10.1101/2020.10.28.20221127 doi: medRxiv preprint 1 Introduction 26 COVID-19 has spread around the world since the outbreak in December 2019, which is caused by SARS-Cov-2, and has attracted the 27 attention of the global because of its high transmission ability, morbidity and mortality [1] [2] [3] [4] . On January 30, the World Health Organization 28 (WHO) identified COVID-19 as a public health emergency of international concern [5] . As of August 31, 2020, a cumulative total of nearly 25 29 million cases and 800,000 deaths have been reported [6] . 30 Lactate dehydrogenase (LDH) is one of the important enzymes in glycolysis and gluconeogenesis. It mainly catalyzes the transformation 31 between lactic acid and pyruvate. Its enzymatic reaction is: pyruvate + NADH+H + ⇌ lactic acid + NAD + . LDH consists of five isozymes 32 composed of different combinations of H and M subunits: LDH1 (H4), LDH2 (H3M), LDH3 (H2M2), LDH4 (HM3) and LDH5 (M4). α-HBDH 33 is tested by the α-ketoacid, a substrate, to determine the LDH activity. Additionally, the activity of LDH1 and LDH2 with more H subunits is 34 described by α-HBDH activity because of the high affinity for this substrate to the H subunit in LDH. α-HBDH mainly distributes in the heart, 35 brain, kidney and red blood cells, and the activity of the enzyme in the heart is more than half of the total enzyme activity, and it level increases 36 in the progression of cor pulmonale, leukemia and tumor. Moreover, the extent of the increase is closely related to the tissue and organ injury, 37 which can be used as an auxiliary diagnostic index in clinical practice [7] [8] [9] [10] [11] . 38 Previous studies have shown that α-HBDH is related to COVID-19. Cen Y et al. observed 1007 mild and moderate COVID-19 patients for 39 28 days. It was found that the higher the α-HBDH value, the greater the risk of progression to severe or critical type [12] . Compared with other 40 pneumonia types, the α-HBDH level in COVID-19 patients was significantly higher, and the α-HBDH value of severe group was higher than 41 that of non-severe group [13, 14] . When complicated with cardiovascular disease or gastrointestinal symptoms, the α-HBDH in COVID-19 patients 42 . CC-BY-NC-ND 4.0 International license It is made available under a who has granted medRxiv a license to display the preprint in perpetuity.

is the author/funder, (which was not certified by peer review) The copyright holder for this preprint this version posted November 1, 2020. ; https://doi.org/10.1101/2020.10.28.20221127 doi: medRxiv preprint 4 was much higher as well [15, 16] . However, there are no reports to study the α-HBDH features in COVID-19 patients during the period from 43 symptom onset, from exposure onset, before and after illness progression and before death. In this study, we analyzed the changes of α-HBDH 44 values in COVID-19 patients during these specific period. 

The pre-designed extraction form was used to obtain the data from hospital information system, and the two groups (two researchers per 55 group) cross-checked one by one. Gender, age, all α-HBDH test results, exact exposure date (accurate to one day), disease onset date, date of 56 transforming to severe and critical type, outcome, death date, etc. were collected. The data within the course of 30 days after symptom onset and 57 40 days after exposure onset were analyzed. The distributions of α-HBDH median value in course/period were plotted with an interval of 1 day, 58 2 days, and 5 days (T1, T2, T3…Tn represented the 5 days unit successively). In this cohort, symptom onset was regarded as disease onset and 59 . CC-BY-NC-ND 4.0 International license It is made available under a who has granted medRxiv a license to display the preprint in perpetuity.

is the author/funder, (which was not certified by peer review) The copyright holder for this preprint this version posted November 1, 2020. ; https://doi.org/10.1101/2020.10.28.20221127 doi: medRxiv preprint 5 the corresponding date was set as the 1st day to record data from symptom onset. For patients with clear exposure date, the exposure date was set 60 as the 1st day to record data when studying the α-HBDH changes from exposure onset. The day when the clinical type changed to severe or 61 critical type was regarded as the "day 0" to study the distribution of α-HBDH before and after the type transformation. The death date was set as 62 "day -1" and selected the -16th day to -1st day as the duration to calculate the α-HBDH median value per two days and plot the distribution 63 when studying the α-HBDH features before death. Two respiratory physicians classified the patients from mild to critical type and then 64 cross-checked, a third expert was involved when there was disagreement. 65 All patients' general information, days from symptom onset to admission to hospital, from symptom onset to transformation to 66 severe/critical type, from severe type to critical type, from symptom onset to death, from symptom onset to discharge, from exposure onset to 67 discharge were included. The α-HBDH median value, abnormal percentage, and distribution of α-HBDH median over time were studied in 68 different course with various initial time, and different periods, including after disease onset, exposure onset, 4 days before and after 69 transformation to severe and critical type, and before death. 

All statistical analyses were performed through SPSS 20.0. Binary data were described using frequency and percentage. The normality of 72 continuous data was checked. Mean and standard deviation were used to describe variables with normal distribution; otherwise, median 73 (interquartile, IQR) was used. Categorical data were described as frequency (%); the chi-square test was applied to assess significance between 74 groups. All graphs were processed by GraphPad Prism 8.0. 75

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The 131 cases underwent 37 laboratory indicators tests in outpatient and hospitalization. This study selected 565 tests of α-HBDH, 86 accounting for 2.30% of the all results of the indicators. The normal range of α-HBDH value is 72-182 U/L. 88 During the first 30 days, there were 506 tests and the α-HBDH median value was 156.33 (125.12-221.59) U/L, and the abnormal percentage 89 was 35.97%. In T1-T6, the abnormal percentage of α-HBDH value was 26.87%, 43.86%, 40.00%, 34.38%, 35.06%, 29.03%, respectively. 90 Among the changes in α-HBDH per day, α-HBDH median value increased from the 1st to the 4th day while decreased during the 15th to the 91 18th day, and fluctuated around upper limits of normal (ULN) from the 4th to the 15th day. And the peak value 191.14 (149.41-223.65) U/L 92 appeared on the 8th day. After the 18th day, α-HBDH median value remained in the normal range, and the outliers on the 21st and the 27th day 93 . CC-BY-NC-ND 4.0 International license It is made available under a who has granted medRxiv a license to display the preprint in perpetuity.

is the author/funder, (which was not certified by peer review) The copyright holder for this preprint this version posted November 1, 2020. ; https://doi.org/10.1101/2020.10.28.20221127 doi: medRxiv preprint 7 might related to some severe or critical cases. According to the change trend per 5 days, the α-HBDH median value had an increasing trend from 94 T1 to T2, and a decreasing trend from T2 to T6. The peak 174.69 U/L appeared on T2. The α-HBDH median value was in the normal range 95 during T1-T6. (Table1,Figure1) 96 97 We followed up all of the cases and finally defined the 42 cases with a exact exposure date. 42 cases underwent 206 tests , and the α-HBDH 103 The date of transforming to severe type was set as "day 0" in 19 severe cases and 18 critical cases, and the changes during 4 days before 104 and after "day 0" was plotted. In the 73 α-HBDH test results, the median value was 235.83 (175.37-331.44) U/L, and the abnormal percentage 105 was 72.60%. The tendency showed that it just slight changed during -4th day (161.95 U/L) to -1st day (175.28 U/L) . Among the period, 106 α-HBDH median value was in the abnormal range except on the -1st day and -4th day. Similarly, the change trend during 4 days before and after 107 transforming to critical type from 18 cases was plotted. The chart showed that the α-HBDH median value was increased from -4th day (216.49 108 U/L) to +2nd day (411.03 U/L) . And all results situated in the abnormal range during the -4th day to +4th day. (Figure2) 109

110 . CC-BY-NC-ND 4.0 International license It is made available under a who has granted medRxiv a license to display the preprint in perpetuity.

is the author/funder, (which was not certified by peer review) The copyright holder for this preprint this version posted November 1, 2020. tendency during T1 to T2, and then gradually decreased, but the results was all in the normal range during T1-T6, which might be the effect of 118 the weak increase of α-HBDH in most mild and moderate patients on the overall data. 119 As shown in the changes per day, the α-HBDH median value increased during the 1st day to 4th day while decreased during the 8th to 12th 120 day and the 15th to 18th day, and it was basically in the normal range after the 16th day. The peak value 191.14 U/L was on the 8th day, 121 abnormal tests were distributed within the 7th to the 9th day and the 13th to the 15th day, the outliers of the 21st day and the 27th day might be 122 related to some severe and critical patients. The α-HBDH median value closed to the ULN on the 4th day since disease course, while the average 123 time from symptom onset to admitted was 4.55±3.11 days, indicating that α-HBDH might have increased 1-2 days before admission. So there 124 might be potential value for diagnosis in the early stage. 125 The time of symptom onset was clear and always regarded as the start of the disease, while the tissue might suffered damage before 126 symptom onset because of the infected virus. Symptom occurs just when the viral load and damage reached a certain extent, thus the total course 127 . CC-BY-NC-ND 4.0 International license It is made available under a who has granted medRxiv a license to display the preprint in perpetuity.

is the author/funder, (which was not certified by peer review) The copyright holder for this preprint this version posted November 1, 2020. ; https://doi.org/10.1101/2020.10.28.20221127 doi: medRxiv preprint should be recorded starting from the day of exposure. After carefully follow-up, it was confirmed that the exposure time of 42 patients in our 128 study could be accurate to a day, and the time from exposure to symptom onset was 11.32±8.48 days. In order to further study the changes of 129 α-HBDH in the whole course including asymptomatic stage, we took the exposure onset as the first day, and performed a time change chart 130 during 40 days after exposure onset. The first test of α-HBDH since exposure onset appeared on the day 8, with the results close to the ULN, 131 indicating that the virus had caused tissue and organ damage before the symptoms onset. On the 18th day, α-HBDH median value reached the 132 peak, indicating that tissue and organ damage accumulated to the maximum degree, and resulting in the highest level of α-HBDH. After the 24th 133 day, α-HBDH median value gradually decreased to the normal range, which might be related to the protective effect of antibody. 134 Due to the differences in the length of incubation period and the progression of disease course, and there was also difference in the time for 135 patients to transform from moderate type to severe type and critical type. In order to reflect the changes of α-HBDH during the transformation 136 from moderate type to severe type and critical type more accurately, we observed and analyzed the changes of α-HBDH during 4 days before 137 and after the transformation. According to the fact that the time for 18 critical patients change from severe to critical type was 3.87±4.78 days, 138 we collected the results tested 4 days before and after the transformation date for statistical analysis. In the severe group, the α-HBDH median 139 value fluctuated at the ULN from the -4th day to -1st day, and there was no obvious change. Moreover, α -HBDH median value rapidly 140 increased and exceeded the ULN from the -1st day to the 4th day, indicating that the tissue and organ injury might be further aggravated after 141 transforming to severe type. Similarly, α-HBDH median value increased from the -4th day to the 2nd day but decreased gradually after the 2nd 142 day in the critical cases, and all results exceeded the ULN within the period, indicating a more serious injury of tissue and organ in this type. 143 The time from symptom onset to death was 18.30±9.65 days, which was relatively dispersed. Thus, it was difficult to describe the features 144 . CC-BY-NC-ND 4.0 International license It is made available under a who has granted medRxiv a license to display the preprint in perpetuity.

is the author/funder, (which was not certified by peer review) The copyright holder for this preprint this version posted November 1, 2020. ; https://doi.org/10.1101/2020.10.28.20221127 doi: medRxiv preprint of α-HBDH before death. In order to study the feature of change in this stage, we performed a time change chart of α-HBDH with the death date 145 as "day -1". The results showed that the α-HBDH median value fluctuated around 320 U/L during the -21st to -5th day, and there was no obvious 146 change. α-HBDH median value increased rapidly 5 days before death, which indicated there was a persistent and irreversible tissue and organ 147 injury before death, Furthermore, aggravated of injury happened within 5 days before death, and α-HBDH value over 320 U/L suggest a high 148 risk of death. 149 α-HBDH distributes in many tissues and organs, mainly in the heart. In clinical work, we usually regard α-HBDH as a kind of myocardial 150 enzyme. The increase of α-HBDH in severe type, critical type and death patients in this cohort indicates there might have the serious tissue and 151 organ damage in these patients, and the higher the α-HBDH, the more serious the illness, and the worse the outcome. 152 However, this study has several limitations. All the patients in the study come from the single hospital, and the sample size is small. And we 153 may fail to detect the daily α-HBDH value in patients and lose some information. 154 5 Conclusion 155 α-HBDH value increases in some COVID-19 patients, obviously in severe type, critical type and death patients, and mainly in 18 days after 156 exposure onset and 10 days after symptom onset. α-HBDH increases 1 day before transforming to severe type, continues to increase in critical 157 type and death patients, increases rapidly 5 days before death. The increase of α-HBDH suggests that COVID-19 patients have tissues and 158 organs damage, mainly in heart. In brief, α-HBDH is an important indicator to judge the severity and prognosis of COVID-19 patients.

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is the author/funder, (which was not certified by peer review) The copyright holder for this preprint this version posted November 1, 2020. ; https://doi.org/10.1101/2020.10.28.20221127 doi: medRxiv preprint Acknowledgements. 160 We thank all colleagues who helped us during the current study. We thank all the medical staff involved in treating the patients and all patients 161 and their families involved in this study. 

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is the author/funder, (which was not certified by peer review) The copyright holder for this preprint this version posted November 1, 2020. ; https://doi.org/10.1101/2020.10.28.20221127 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a who has granted medRxiv a license to display the preprint in perpetuity.

is the author/funder, (which was not certified by peer review) The copyright holder for this preprint this version posted November 1, 2020. ; https://doi.org/10.1101/2020.10.28.20221127 doi: medRxiv preprint 13 Figure 1 . Changes of α-HBDH during the total course 173 . CC-BY-NC-ND 4.0 International license It is made available under a who has granted medRxiv a license to display the preprint in perpetuity.

is the author/funder, (which was not certified by peer review) The copyright holder for this preprint this version posted November 1, 2020. ; https://doi.org/10.1101/2020.10.28.20221127 doi: medRxiv preprint Figure 2 . (A) Changes of α-HBDH since exposure onset, (B) Changes of α-HBDH before and after transforming to severe or critical type, (C) 174 Changes of α-HBDH before death.

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