key: cord-298534-1j8jkfn9
authors: Zhu, H.; Qu, G.; Yu, H.; Huang, G.; Chen, L.; Zhang, M.; Wan, S.; Pei, B.
title: Features of alpha-HBDH in COVID-19 patients with different ages,outcomes and clinical types: a cohort study
date: 2020-11-03
journal: nan
DOI: 10.1101/2020.10.29.20222612
sha: 
doc_id: 298534
cord_uid: 1j8jkfn9

Background: Coronavirus disease-2019 (COVID-19) has spread all over the world and brought extremely huge losses. At present, there is no study to systematically analyse the features of hydroxybutyrate dehydrogenase (alpha-HBDH) in COVID-19 patients with different ages, clinical types and outcomes. Methods: Electronic medical records including demographics, clinical manifestation, alpha-HBDH test results and outcomes of 131 hospitalized COVID-19 patients, with confirmed result of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection, were extracted and analyzed. Results: The alpha-HBDH value in greater than or equal to 61 years old group, severe group and critical group, death group all increased at first and then decreased, while no obvious changes were observed in other groups. And there were significant differences of the alpha-HBDH value among different age groups, clinical type groups and outcome groups. The optimal scale regression model showed that alpha-HBDH value and age were related to clinical type. Conclusions: alpha-HBDH value increases in some COVID-19 patients, obviously in greater than or equal to 61 years old, death and critical group, indicating that patients in these three groups suffer from more serious tissues and organs damage, higher alpha-HBDH value and risk of death. The obvious difference between death and survival group in early stage may provide a approach to judge the prognosis. The accuracy of the model to distinguish severe/critical type and other types is 85.84%, suggesting that alpha-HBDH could judge the clinical type of COVID-19 patients accurately. In brief, alpha-HBDH is an important indicator to judge the severity and prognosis of COVID-19.

Since the outbreak of COVID-19 in December 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it 27 has spread rapidly around the world. SARS-Cov-2 has attracted the attention of the global because of its high transmission ability, 28 morbidity and mortality [1] [2] [3] [4] . On January 30, the World Health Organization (WHO) identified COVID-19 as a public health emergency of 29 international concern [5] . As of July 1, 2020, the number of confirmed cases of COVID-19 worldwide has reached 10357622, and the 30 number of deaths has reached 508055 [6] . 31 Lactate dehydrogenase (LDH) is one of the important enzymes in glycolysis and gluconeogenesis. It mainly catalyzes the 32 transformation between lactic acid and pyruvate. Its enzymatic reaction is: pyruvate + NADH+H + ⇌ lactic acid + NAD + . LDH consists of 33 five isozymes composed of different combinations of H and M subunits: LDH1 (H4), LDH2 (H3M), LDH3 (H2M2), LDH4 (HM3) and 34 LDH5 (M4). α-HBDH is tested by the α-ketoacid, a substrate, to determine the LDH activity. Additionally, the activity of LDH1 and 35 LDH2 with more H subunits is described by α-HBDH activity because of the high affinity for this substrate to the H subunit in LDH. 36 α-HBDH mainly distributed in the heart, brain, kidney and red blood cells, and the activity of the enzyme in the heart is more than half of 37 the total enzyme activity. α-HBDH level increased in the progression of cor pulmonale, leukemia and tumor. Moreover, the extents of the 38 increase and the tissue and organ injury were closely related, which can be used as an auxiliary diagnostic index [7] [8] [9] [10] [11] . 39 Compared with other pneumonia types, the α-HBDH level in COVID-19 patients was significantly higher, and the α-HBDH value of 40 severe group was higher than that of non-severe group [12, 13] . When complicated with cardiovascular disease or gastrointestinal symptoms, 41 the increase of α-HBDH in COVID-19 patients was much more significant as well [14, 15] . Cen Y et al. observed 1007 mild and moderate 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 3, 2020. ; https://doi.org/10.1101/2020.10.29.20222612 doi: medRxiv preprint COVID-19 patients for 28 days. It was found that the higher the α-HBDH value, the greater the risk of progression to severe or critical 43 type [16] . Zhang Gemin et al. divided 95 COVID-19 patients into four groups according to their α-HBDH level on admission. They found 44 that the higher the α-HBDH value, the greater the proportion of severe cases, and the higher the risk of death or need for mechanical 45 ventilation for patients, showing that the high α-HBDH level indicates an increased risk of further aggravation of the disease [17] . In this 46 study, we analyzed the changes of α-HBDH values of COVID-19 patients with different ages, clinical types and outcomes. The effects of α-HBDH, age and gender on the clinical type of COVID-19 patients were quantified by the optimal scale regression model, so as to 48 achieve the purpose of early judging the severity of the disease. 

Our study included individuals with complete examination data, 18 years old or above, who were hospitalized in Xiangyang No.1 52 People's Hospital with a diagnosis of COVID-19. In the end, we included a total of 131 patients. 53 54 This research project was a bidirectional observational cohort study. According to the diagnosis and treatment guidelines [18] , the patients 55 were divided into mild group, moderate group, severe group and critical group. According to their age, the patients were divided into ≤40 years 56 old group, 41-60 years old group and ≥61 years old group. According to the outcome, the patients were divided into death group and survival 57 group. The distributions of α-HBDH median value were plotted with an 5-days interval (T1, T2, T3…Tn represented the time unit successively). 58 The symptom onset data was designed as the first day of disease, the abnormal percentage, median and quartile interval of α-HBDH in different 59 ages, outcomes and clinical types were calculated. 60 . 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 3, 2020. 64 Two groups (two researchers per group) extracted the data from hospital information system through a consistent data collection protocol 65 and cross-checked. Gender, age, all α-HBDH test results, disease onset date, outcome, death date, etc. were collected. Two respiratory 66 physicians classified the clinical types and then cross-checked the results. A third expert was involved when there was disagreement. The data 67 were traced back to 23 January and followed up to 28 March, 2020. 68 69 All statistical analyses were performed by SPSS 20.0. Continuous data in accordance with normality were represented by means and 70 standard deviations, otherwise median (interquartile, IQR) was applied. Categorical data were described as frequency (%). The chi-square test 71 was conducted to assess significance between groups. T-test was used to compare the quantitative data of normal distribution between the two 72 groups, and the comparison of the quantitative data of non-normal distribution between the two groups was analyzed using Mann-Whitney U test. 73 The correlation between two variables was tested by Spearman correlation test. The maximum α-HBDH value in the first 15 days, age and 74 gender were regarded as independent variables and clinical types were regarded as dependent variables to build the optimal scale regression 75 model. 76 

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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 3, 2020. ; https://doi.org/10.1101/2020. 10 85 In ≤40 years old group, 41-60 years old group and ≥61 years old group, the α-HBDH median value was 123. 17 and 60.70%, respectively. The changes indicated that the α-HBDH median value in ≤40 years old group increased during T1-T2 and decreased 88 after T2, and the normal range was T1 to T6; in 41-60 years old group, the α-HBDH median value decreased during T1-T6, and was in the 89 normal range from T1 to T6; in ≥61 years old group, the α-HBDH median value increased during T1-T2 and decreased after T2, and the 90 abnormal time interval was T2-T5 (Figure1, Table1). 91 There were significant differences of the α-HBDH value in the first 30 days among the three age groups. Significant differences were 92 observed in the α-HBDH value between ≤40 years old group and 41-60 years old group during T1-T4, between ≤40 years old group and ≥61 93 years old group during T1-T6, and between 41-60 years old group and ≥61 years old group during T2-T6. Differences were also significant in 94 the α-HBDH value abnormal percentage among the three age groups (P<0.001). The age was correlated with α-HBDH value according to the 95 Spearman correlation test (P<0.001), and the coefficient was 0.52.

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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 3, 2020. ; https://doi.org/10.1101/2020.10.29.20222612 doi: medRxiv preprint 97 In survival group and death group, the α-HBDH median value was 147.80 (121.55-194.67) U/L and 337.18 (294.01-477.11) U/L, 98 respectively, and the α-HBDH value abnormal percentage was 29.52% and 96.08%, respectively. The changes indicated that the α-HBDH 99 median value in survival group increased during T1-T2, decreased after T2, and was in the normal range during T1-T6; while in death group, the 100 α-HBDH median value increased during T1-T4 and decreased after T4, and the abnormal time interval was T1-T6 (Figure1, Table2). 101 There were significant differences of the α-HBDH in the first 30days and every time unit during T1-T6. Differences were also significant in 102 the α-HBDH value abnormal percentage among the two outcome groups (P<0.001). Spearman correlation test showed that there was a 103 correlation between outcome groups and the α-HBDH value (P<0.001), and the correlation was 0.49. 104 increased during T1-T2 and decreased after T2, and was in the normal range during T1-T6; in the severe group, the α-HBDH median value 109 increased during T1-T3 and decreased after T3, and the abnormal time interval was T2-T4; in the critical group, the α-HBDH median value 110 increased during T1-T3 and decreased after T3, and the abnormal time interval was T1-T6 (Figure1, Table3) . However, the mild group was 111 excluded in statistical analysis for the reason that it only contained 4 cases. 112 There were significant differences of the α-HBDH value in the first 30 days among the three clinical type groups. Significant differences 113 were observed in the α-HBDH value between moderate type group and severe type group during T1-T6, between moderate type group and 114 . 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 3, 2020. ; https://doi.org/10.1101/2020.10.29.20222612 doi: medRxiv preprint critical type group during T1-T6, and between severe type group and critical type group during T2-T6. gender, respectively). The comparison between the output type and the actual type quantification score was shown in the figure 2. According to 121 the model, the output accuracy of moderate, severe and critical types was 81.45%. In order to discriminate moderate type and severe/critical type, 122 the severe type and critical type were combined to the same category, and the accuracy was 85.84%. 123 4 Discussion 124 α-HBDH is one of the important enzymes in the process of glucose metabolism, which is widely distributed in various tissues and organs, 125 especially in the heart, brain, kidney and red blood cells. COVID-19 mainly induces lung injury and causes damage to the heart and other tissues 126 and organs, which results in the release of α-HBDH and the increase of α-HBDH in blood terminally [17] . The α-HBDH value in COVID-19 127 patients changed, it increased or significantly increased in some patients (Figure1). In different age groups, outcome groups and clinical type 128 groups, there were significant differences in the distribution and abnormal percentage of α-HBDH. Age and outcome were significantly 129 correlated with α-HBDH. Moreover, α-HBDH value may be related to the severity of COVID-19. 130 In ≥61 years old group and death group, the α-HBDH median value increased from T1, and reached a single peak in T2 (258.66 U/L) and 131 T4 (455.11 U/L), respectively, which was significantly different from that in ≤40 years old group (peak value was 144.26 U/L ), 41-60 years old 132 . 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 3, 2020. ; https://doi.org/10.1101/2020.10.29.20222612 doi: medRxiv preprint group (peak value was 174.26 U/L) and survival group (peak value was 165.02 U/L). The abnormal interval of α-HBDH median value in ≥61 133 years old group and death group was T1-T5, T1-T6 respectively, which was significantly different from that in ≤40 years old group, 41-60 years 134 old group and survival group, in which α-HBDH median value were all in the normal range. It shows that the older the age, the worse the 135 outcome, the higher the α-HBDH value, and the longer the abnormal interval. The α-HBDH value in ≥61 years old group and death group was 136 higher than that in other groups, indicating that the injury of heart, brain, kidney and other tissues and organs is more serious in elderly and death 137 patients, which was consistent with previous study [19] . This may be related to the poor function of the immune system and being more sensitive The α-HBDH median value of the mild group was in the normal range, without obvious change, indicating that the injury of tissue and 144 organ injury in this type was slight. The same as mild group, α-HBDH median value in moderate group also distributed in the normal range. It 145 increased firstly, and reached a peak (133.20 U/L) in T2, indicating that tissue and organ injury occurred immediately after the symptom onset in 146 spite of the slight degree, and mainly occurred in the first 10 days. The changes of α-HBDH median value of severe group was similar to that of 147 critical group, which increased during T1-T3 and decreased after T3. Their peak value was 222.56 U/L and 355.23 U/L appearing in T3, and 148 recovered to normal range in T5 and T7, respectively. It shows that the more serious the illness, the higher the α-HBDH median value and peak 149 . 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 3, 2020. ; https://doi.org/10.1101/2020.10.29.20222612 doi: medRxiv preprint value, the longer the abnormal interval, which may be related to the serious virus-induced acute lung injury, tissues and organs damage in severe 150 and critical type groups. These characteristics are of great significance for us to judge the severity of the disease by α-HBDH. 151 The maximum α-HBDH value in the first 15 days, age and gender of all patients were selected to build the optimal scale regression model. 152 α-HBDH <250.17 U/L and aged <60 years old was associated with moderate type, α-HBDH between 259.88-311.73 U/L and aged between 153 62-70 years old was associated with severe type, α-HBDH >327.71 U/L and aged >70 years old was associated with critical type. In this model, 154 the output accuracy for clinical type was over 80%, which indicated that the model could distinguish the clinical classification based on our data 155 well. α-HBDH and age could be used to discriminate the clinical type of COVID-19 patients if further verified by other data, which could help 156 us to grasp the opportunity of treatment and reduce the risk of progression to severe and critical type in early stage. 157 However, this study has several limitations. All the patients in the study come from the single hospital, and the sample size is small. This 158 study is a retrospective cohort study, which fails to detect and analyze the daily α-HBDH in patients and may lose some information. 159 

160 α-HBDH value increases in some COVID-19 patients, obviously in ≥61 years old, death and critical group, indicating that patients in these 161 three groups suffer from more serious tissues and organs damage, higher α -HBDH value and risk of death. The obvious difference between 162 death and survival group in early stage may provide a approach to judge the prognosis. The accuracy of the model to distinguish severe/critical 163 type and other types is 85.84%, suggesting that α-HBDH could judge the clinical type of COVID-19 patients accurately. In brief, α-HBDH is 164 an important indicator to judge the severity and prognosis of COVID-19.

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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 3, 2020. . 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 3, 2020. Score: quantitative score in optimal scale regression model . 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 3, 2020. ; https://doi.org/10.1101/2020.10.29.20222612 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 3, 2020. ; https://doi.org/10.1101/2020. 10.29.20222612 doi: medRxiv preprint Figure2. Comparison between the output type and the actual type quantification score in the model . 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 3, 2020. ; https://doi.org/10.1101/2020.10.29.20222612 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 3, 2020. ; https://doi.org/10.1101/2020.10.29.20222612 doi: medRxiv preprint

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