*Contributed equally
Lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) are important indicators of cardiovascular, muscle and liver lesions, and can be used as prognostic indicators for infectious diseases, such as coronavirus disease 2019 (COVID-19). The present systematic review and meta-analysis assessed the prognostic value of LDH and AST levels for COVID-19 severity. Ovid-Medline, PubMed, Embase and The Cochrane Library were used to search for articles, according to the inclusion and exclusion criteria, until July 2022. The meta-analysis was performed using Revman5.3 and Stata15.1. Standardized mean difference (SMD) and 95% confidence intervals (CIs) of LDH and AST concentrations were analyzed using a random-effects model. Heterogeneity was investigated using meta-regression and subgroup methods. A total of 4,342 patients with COVID-19 in 23 articles were included in the present study. LDH (SMD=1.21; 95% CI: 0.98, 1.44) and AST (SMD=0.68; 95% CI: 0.54, 0.81) were significantly higher in patients with severe COVID-19 compared with in those with non-severe COVID-19. Serum LDH and AST levels in critically ill patients with COVID-19 were increased, suggesting a correlation between the levels of LDH and AST and the severity of COVID-19. These findings may help to develop a risk-stratified approach to the care of patients with this disease.
Coronavirus disease 2019 (COVID-19) has become a global pandemic; as of December 2022, over 600 million confirmed cases, including six million deaths, were reported to WHO (
The population is generally susceptible to COVID-19, and some immunity can be improved after infection or vaccination against the new coronavirus (
Myocardial damage in COVID-19 patients is closely related to the severity of the disease and even the prognosis. Therefore, early monitoring of cardiac damage by biomarkers is recommended after hospitalization for COVID-19 infection in patients with pre-existing CVD. Lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) are traditional markers of myocardial injury. There have been several studies assessing the utility of biomarkers indicating severe COVID-19. Fialek
Our work followed the PRISMA guidelines for reporting systematic reviews and meta-analyses (
Studies were included if they: i) Observational studies (cohort, case-control, cross-sectional); ii) Patients were diagnosed with COVID-19 by qPCR (quantitative real-time PCR); iii) Reported outcomes in the form of markers to LDH and AST; iv) Investigation of binary outcomes like ICU versus non-ICU admission, severe versus non-severe disease, in-hospital mortality versus discharged alive and survivors.
Exclusion criteria were: i) Lack of information on LDH and AST levels at the initial diagnosis or follow-up; ii) Studies investigated pregnant women or children; iii) No clear grouping of outcome indicators; iv) Letters, reviews, conference proceedings, guidelines, duplicate publications, or other unrelated topics are outside the scope of this review.
Two investigators (ZYH and RQY) independently reviewed the abstracts. A full-text review was conducted when a given abstract were considered potentially relevant. If there is a disagreement between investigators, the third author (SKY) gives suggestions. The two investigators (ZYH and RQY) reviewed whole papers independently against the inclusion criteria, and if necessary, any discrepancies were decided by the third author (SKY). Throughout the screening, the first author's name, publication date, the number of individuals enrolled, the nation or region, the patients' basic information (mostly gender and age), and the LDH and AST levels were separately collected by the two investigators from the included studies. To assess study quality, we used the Newcastle-Ottawa Scale (NOS), with a score above six considered high quality (
The forest plots of standard mean difference (SMD) were used to analyze the differences in LDH and AST concentrations between patients with severe and non-severe COVID-19. The raw data has been processed to the median and IQR values, making them acceptable for analysis (
A flowchart illustrating the filtering procedure is shown in
Essential information included in the study is shown in
The LDH concentrations heterogeneity test results show high heterogeneity between studies (
We did a sensitivity analysis and applied the leave-one-out method to evaluate each study's influence. The heterogeneity was found to be considered regardless of whatever study was omitted. Both LDH and AST sensitivity analyses revealed no significant differences between studies. The pooled SMD values did not change after the sequential removal of individual studies (
We used funnel plots and Egger's tests to evaluate publication bias. Using Egger's test, no significant publication bias was found for all included AST studies (P=0.155), but LDH has (P=0.015). The funnel plot also showed the difference between the two groups (
The effect estimate did not differ substantially with outcomes (LDH P=0.909, AST P=0.851), publication year (LDH P=0.383, AST P=0.977), region (LDH P=0.261, AST P=0.533), and age (LDH P=0.301, AST P=0.716) according to meta-regression (
A higher proportion of men with severe COVID-19 was found in the subgroup analysis (RD 0.21; 95% CIs: 0.06, 0.35; P<0.001) (
LDH catalyzes the conversion of pyruvate (the end product of glycolysis) to lactate, reversing the liver's Cori cycle when hypoxia or insufficient supply occurs (
The time-dependent concentration of AST also has strong sensitivity and specificity to acute myocardial injury. A multi-center retrospective study showed that the mortality rate of AST abnormalities in COVID-19 patients was higher than that of other patients. This result recommended using AST to monitor COVID-19 patients immediately (
It is worth noting that both LDH and AST have widespread activities in numerous body tissues, and they are also typical markers of sepsis. What is certain is that they are indeed elevated in patients with severe COVID-19. The potential causes of cardiac injury in COVID-19 patients are diverse, such as direct viral damage to cardiomyocytes, cytokines and interferon-induced inflammation, myocardial interstitial fibrosis, T-cell responses, disruption of ACE-2 receptors. Moreover, the lung injury may cause damage to cardiac muscle cells due to hypoxia, and continued disruption of endothelial function negatively affect the thrombotic/fibrinolytic balance (
The systematic review and meta-analysis showed that LDH and AST serum concentrations were considerably higher in COVID-19 patients with severe disease than in non-severe. These findings show that LDH and AST could be employed as possible predictors of prognosis and risk of death in patients with COVID-19. However, as most of the studies in the current review were retrospective and had significant heterogeneity, bigger sample sizes and high-quality prospective cohort studies are required to confirm this finding.
The authors would like to thank Professor Richard Pang for checking the language usage, grammar, punctuation and spelling of this article.
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
SKY, LZ and FZ conceptualized and designed the study. ZYH and RQY collected data and drafted the manuscript. JSL, HBD and YLZ analyzed and interpreted data. SKY gave final approval of the version to be published. ZYH and RQY confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.
Not applicable.
Not applicable.
The authors declare that they have no competing interests.
Flow diagram illustrating the filtering procedure according to PRISMA. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Forest plots depicting different LDH concentrations in the severe group vs. the non-severe group. The diamond represents the point estimate and CIs after combining and averaging all individual studies. LDH, lactate dehydrogenase; SD, standard deviation; Std. Mean Difference, standardized mean difference; IV, inverse variance; CI, confidence interval; df, degree of freedom.
Forest plots depicting different AST levels in the severe group vs. the non-severe group. The diamond represents the point estimate and confidence intervals after combining and averaging all individual studies. AST, aspartate aminotransferase; SD, standard deviation; Std. Mean Difference, standardized mean difference; IV, inverse variance; CI, confidence interval; df, degree of freedom.
Sensitivity analysis for (A) LDH and (B) AST and coronavirus disease 2019 severity. The hollow circles represent the pooled SMD when the given named study is omitted from the meta-analysis. The middle vertical axis indicates the overall SMD and the two vertical axes indicate the 95% CIs. AST, aspartate aminotransferase; CI, confidence interval; LDH, lactate dehydrogenase; SMD, standardized mean difference.
Funnel plot for the study evaluating the relationship between (A) lactate dehydrogenase and (B) aspartate aminotransferase concentrations with coronavirus disease 2019 severity status. SMD, standardized mean difference.
Baseline characteristics of COVID-19 patients from included studies.
Severe group | Non-severe group | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
First author (year) | Region | Number | Mean age, years (SD) | Male, % | Mean LDH level, U/l (SD) | Mean AST level, U/l (SD) | Number | Mean age, years (SD) | Male, % | Mean LDH level, U/l (SD) | Mean AST level, U/l (SD) | NOS | (Refs.) |
Akdogan D (2021) | Turkey | 57 | 51.6 (12.9) | NA | 241.5 (82.4) | 30.0 (14.9) | 118 | 38.6 (11.9) | NA | 191.4 (37.5) | 27.2 (18.1) | 6 | ( |
Ayten O (2020) | Turkey | 27 | 64.3 (12.0) | 74.0 | 830.4 (480.2) | 42.4 (26.3) | 46 | 52.6 (12.2) | 58.7 | 511.6 (271.7) | 28.1 (14.2) | 5 | ( |
Kantri A (2021) | Morocco | 45 | 65.0 (13.0) | 77.8 | 327.3 (111.8) | 36.5 (27.2) | 89 | 42.3 (20.3) | 42.7 | 210.3 (66.3) | 20.7 (11.3) | 7 | ( |
Azizmohammadi S (2021) | Iran | 63 | 59.8 (14.1) | 74.6 | 311.3 (82.7) | 33.3 (10.6) | 176 | 43.9 (14.5) | 48.9 | 213.7 (75.5) | 27.0 (10.5) | 6 | ( |
Wang D (2020) | China | 71 | 62.3 (12.1) | 62.0 | 349.3 (162.7) | 63.8 (32.9) | 72 | 45.3 (21.2) | 40.3 | 208.0 (78.7) | 43.2(20) | 6 | ( |
Sepulchre E (2022) | Belgium | 60 | 66.5 (14.4) | 71.7 | 510.3 (208.1) | 66.7 (46.3) | 138 | 60.3 (20.2) | 52.2 | 342.7 (173.1) | 42.0 (28.5) | 8 | ( |
Zheng F (2020) | China | 30 | 56.5 (15.2) | 46.7 | 244.9 (94.7) | 35.6 (18.3) | 131 | 40.3 (14.2) | 50.4 | 168.0 (56.0) | 23.7 (7.3) | 5 | ( |
Pan F (2020) | China | 89 | 67.7 (9.0) | 75.3 | 516.0 (108.1) | 50.0 (23.4) | 35 | 63.7 (21.6) | 51.4 | 378.0 (195.6) | 48.0 (35.6) | 7 | ( |
Fukushima K (2021) | Japan | 41 | 67.3 (18.4) | 90.2 | 467.7 (153.9) | 53.7 (28.4) | 193 | 44.0 (20.9) | 60.6 | 232.8 (82.9) | 28.0 (13.4) | 7 | ( |
Bonetti G (2020) | Italy | 70 | 75.4 (15.0) | 64.3 | 524.0 (166.0) | 62.8 (29.5) | 75 | 62.6 (15.0) | 68.9 | 320.1 (111.8) | 43.0 (25.7) | 7 | ( |
Wang H (2021) | China | 24 | 55.7 (15.0) | 62.5 | 267.5 (122.6) | 32.4 (11.3) | 37 | 51.0 (17.0) | 43.2 | 181.2 (32.7) | 22.0 (11.3) | 8 | ( |
Huang H (2021) | China | 21 | 61.4 (16.4) | 57.1 | 356.9 (204.6) | 37.0 (30.2) | 43 | 41.2 (15.7) | 58.1 | 209.2 (52.2) | 25.0 (6.9) | 7 | ( |
Kumar H (2021) | India | 30 | 58.9 (13.2) | 60.0 | 617.9 (389.4) | 81.3 (51.1) | 79 | 56.1 (16.6) | 79.7 | 448.8 (185.9) | 66.5 (33.6) | 7 | ( |
Gómez LC (2021) | Spain | 166 | 76.0 (14.2) | n | 377.3 (170.1) | 31.0 (16.4) | 376 | 64.0 (12.7) | n | 276.8 (110.3) | 31.0 (16.4) | 9 | ( |
Vidal-Cevallos P (2021) | Mexico | 79 | 46.7 (25.7) | 78.5 | 577.0 (269.6) | 76.3 (80.0) | 298 | 41.8 (22.7) | 72.1 | 389.8 (191.8) | 45.3 (22.7) | 6 | ( |
Mo P (2021) | China | 85 | 60.7 (14.3) | 64.7 | 306.7 (181.7) | 29.0 (18.9) | 70 | 45.0 (17.4) | 44.3 | 259.0 (106.0) | 22.7 (13.6) | 9 | ( |
Snipelisky D (2020) | Georgia | 42 | 61.9 (15.5) | 66.7 | 463.0 (224.0) | 66.0 (48.0) | 144 | 60.5 (17.7) | 39.6 | 361.0 (242.0) | 38.0 (22.0) | 7 | ( |
Qin W (2021) | China | 23 | 69.3 (7.1) | 43.5 | 458.4 (136.5) | 37.9 (23.7) | 239 | 61.3 (12.2) | 47.3 | 245.0 (80.6) | 25.3 (11.9) | 7 | ( |
Zhang W (2021) | China | 16 | 51.2 (14.1) | 68.8 | 759.7 (315.4) | 31.1 (17.2) | 49 | 43.6 (14.2) | 53.1 | 438.3 (71.0) | 23.7 (9.2) | 5 | ( |
Feng X (2020) | China | 20 | 69.2 (11.1) | 65.0 | 665.7 (388.6) | 62.8 (68.0) | 94 | 62.8 (13.7) | 61.7 | 285.3 (127.1) | 40.6 (23.5) | 6 | ( |
Zhu Y (2020) | China | 29 | 72.6 (13.2) | 65.5 | 785.5 (274.4) | 51.0 (50.0) | 73 | 62.2 (13.6) | 53.4 | 352.1 (140.9) | 32.0 (13.0) | 8 | ( |
Yousaf MN (2022) | Pakistan | 135 | 56.5 (16.3) | n | 702.0 (375.0) | 49.0 (37.0) | 251 | 52.7 (16.0) | n | 498.0 (348.0) | 41.0 (21.0) | 9 | ( |
Wang Z (2020) | China | 116 | 72.7 (12.0) | 56.0 | 475.5 (203.4) | 42.0 (23.3) | 177 | 49.6 (22.2) | 41.2 | 231.3 (71.2) | 26.3 (10.5) | 9 | ( |
LDH, lactate dehydrogenase; AST, aspartate aminotransferase; NA, not available; NOS, Newcastle-Ottawa Scale. Data presented as mean (SD).
Meta-regression analysis in different subgroups.
LDH | AST | |||||
---|---|---|---|---|---|---|
Subgroup | Coef | Std. Err. | Coef | Std. Err. | ||
Outcomes | -.0371399 | .3256605 | 0.909 | -.0333406 | .1769221 | 0.851 |
Publication year | .5294593 | .6070254 | 0.383 | .0099645 | .3463723 | 0.977 |
Region | -.367411 | .3268494 | 0.261 | -.1122298 | .1800766 | 0.533 |
Age | .3303795 | .31914 | 0.301 | -.0628999 | .1726357 | 0.716 |
LDH, lactate dehydrogenase; AST, aspartate aminotransferase; Coef, coefficient; Std. Err., standard error.