The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome-coronavirus-2, originally emerged from China, has documented 274,628,461 confirmed cases and 5,358,978 deaths globally, and 34,752,164 confirmed cases 478,007 deaths in India. Identification of laboratory predictors of progression toward severity and fatality is needed for an efficient management of patients with COVID-19.[2,3] In this effect, several biochemical analytes that show abnormal values in severely affected patients have been proposed as disease biomarkers, including among others’ serum.[4–10]
COVID-19 pneumonia is a heterogeneous disease with variable effect on lung parenchyma, airways, and vasculature leading to long-term effects on lung functions. Although lung is the primary target organ involvement in COVID-19, many patients were having pulmonary and extrapulmonary effects due to immune activation pathway and direct virus-induced lung damage. In COVID-19 pneumonia, pathophysiology constitutes different pathways such as immune activation, inflammatory, thrombogenic, and direct viral affection to lungs and extrapulmonary tissues.
In the last few decades, lactate dehydrogenase (LDH) has been analyzed as a prognostic marker in hematology and oncology, in hemolytic anemia, in megaloblastic anemia, Hodgkin disease and non-Hodgkin lymphoma, and leukemias. Elevated LDH levels are the product of enhanced glycolytic activity of the tumor and tumor necrosis due to hypoxia, the latter being associated with high tumor burden. LDH has many subtypes, 1 5 released by erythrocytes, heart and skeletal muscles. It’s isolation usually done as a major component and subtyping is not routinely required. Severe infections including interstitial pneumonia or acute respiratory distress syndrome (ARDS) may cause tissue damage induced by cytokine production with subsequent release of LDH into the bloodstream.[15,16]
Overall, 5% of COVID 19 pneumonia cases are at high risk of death those require intensive care unit treatment including mechanical ventilation. Therefore, markers with high positive predictive value for early prediction of ARDS will help in decreasing mortality. In inflammatory panel evaluation, LDH has a very well association with direct lung damage and significantly raised in more widespread tissue injury.[18,19] In a recently published study on a large case series of COVID-19 patients, the documented high serum concentrations of LDH were associated with more chance of death due to pneumonia.
In the present study, we have utilized LDH as a ‘core marker’ with other inflammatory markers in laboratory panel in all COVID 19 patients. Additionally, we have studied role of LDH in analysing response to treatment and predicting of post COVID fibrosis.
Materials and Methods
A prospective, observational, follow-up study, conducted during July 2020 to May 2021 in two centers, Pulmonary Medicine, MIMSR Medical College and Venkatesh Hospital, Latur, India, included 1000 COVID-19 cases confirmed with real-time reverse transcription polymerase chain reaction (RT-PCR), to find out the role of LDH in predicting severity of illness, assessing response to therapy and outcome as post-COVID fibrosis in diagnosed COVID-19 pneumonia cases admitted in critical care unit. Total 1000 cases were enrolled in the study after IRB approval and written informed consent of all included cases were taken at a respective center of study in Venkatesh Hospital and MIMSR Medical College, Latur.
This study was approved by the Institutional Review Board/Ethics Committee at Venkatesh Hospital and Critical Care Center, Latur, India, and MIMSR Medical College, Latur, India (Approval # VCC/98-2020-2021; Approval Date: July 28, 2020).
Inclusion criteria: COVID 19 RT-PCR confirmed cases hospitalised in indoor units and intensive care units with age more than 18 years. Cases with or without comorbidities and irrespective of severity of illness and oxygenations status were enrolled. Exclusion criteria: Those not willing to give consent, not able to perform LDH, and not willing to remain in follow-up were excluded from the study.
All study cases were undergone the following assessment before enrolling in the study [Figure 1]
COVID 19 RT PCR test was performed on nasopharyngeal samples collected with all standard institutional infection control policies. If the first test results were negative and radiological features clearly documenting pneumonia then we have repeated the RT PCR test and enrolled all cases with positive COVID 19 RT PCR test. HRCT of the thorax to assess the severity of lung involvement, and categorized as mild if score 15 or 15–25. Clinical assessment, routine biochemistry and haematological workup with viral inflammatory markers as C reactive protein (CRP), ferritin, LDH, interleukin 6 (IL 6) titers. Entry point LDH titer was utilized as an assessment tool of severity of illness with clinical parameters. If LDH analysis was normal at entry point, then LDH titer was repeated on the day of discharge from hospital or done during hospitalization if clinical course deteriorates. If LDH analysis was abnormal at entry point, we repeated on every 72 h as follow-up to assess severity, progression of illness, and also titer level utilized to assess response to medical treatment. Follow-up HRCT thorax was done after 12 weeks or 3 months of discharge from hospital for analysis of post-COVID lung fibrosis in selected cases with abnormal LDH level at discharge and required bilevel-positive airway pressure/noninvasive ventilation (BIPAP/NIV) during hospitalization and cases required oxygen supplementation at home.
Methodology of lactate dehydrogenase titer assessment
During LDH evaluation, Kinetic/quantitative principal method of analysis were done on serum samples. Serum samples were processed by Rosche Biochemistry analyser and utilized Spinreact diagnostic kits.
- Principle: Lactate to pyruvate (NADH)
- Normal values: Normal values 70-470 mg/dL.
Interpretation of results
- Normal: LDH value up to 470 mg/L
- Positive: Value above 470 mg/dL
- Significant: Two-fold raised LDH level
- Highly significant: Four-fold raised LDH level
- Follow-up significance: Values raised or decreased in two-to-four-fold change.
The statistical analysis was done by using Chi-square test in R-3.4 software. Significant values of χ2 were seen from probability table for different degrees of freedom required. P value was considered significant if it was below 0.05 and highly significant in case if it was <0.001.
In the present study, 1000 COVID-19 pneumonia cases were confirmed by COVID-19 RT-PCR, males were 650/1000 and females were 350/1000, and age >50 were 600 cases and age <50 were 400 cases. A significant association in LDH and COVID-19 pneumonia has been documented with variables such as age, gender, diabetes mellitus, ischemic heart disease (IHD), hypertension, chronic obstructive pulmonary disease (COPD), and obesity (P < 0.00001) [Table 1].
Results: Core observations
HRCT thorax severity score at entry point with LDH level has a significant association in COVID-19 pneumonia cases (P < 0.00001) [Table 3]. LDH level has a significant association with duration of illness (Doi) in COVID-19 pneumonia cases (P < 0.00001) [Table 2]. LDH level has a significant association with oxygen saturation in COVID-19 pneumonia cases (P < 0.00001) [Table 4]. BIPAP/NIV requirement during course of COVID-19 pneumonia in critical care setting has a significant association with LDH level (P < 0.00001) [Table 5]. Timing of BIPAP/NIV requirement during course of COVID-19 pneumonia in critical care setting has a significant association with LDH level (P < 0.00001) [Table 6]. Follow-up LDH titer during hospitalization as compared to entry point abnormal LDH has a significant association in post-COVID lung fibrosis (P < 0.00001) [Table 7]. Follow-up LDH titer during hospitalization as compared to entry point normal LDH has a significant association in post-COVID lung fibrosis (P < 0.00001) [Table 8].
Association of computerized tomography severity (at entry point) and LDH in COVID-19 cases
We have documented that CT severity can be considered the best visual marker of severity of COVID-19 pneumonia which can be correlated with inflammatory markers such as LDH and it will help in triaging cases in casualty and help in targeting interventions in indoor units accordingly to have successful treatment outcome. We have also documented LDH level help in predicting extent of lung involvement. In present study we have observed significantly raised value with more lung damage i.e. anatomical extent is proportional to LDH level. We have also noted that more the anatomical involvement, more lung inflammatory damage and resultant hypoxia is further trigger for exaggerated LDH levels due to increased anaerobic metabolism. Magdy et al., Huang et al., Salvador et al., Tao et al., Lv XT et al., Tordjman et al., Boldt et al., Deng et al., Xi et al., and Cho et al. have documented similar observations in their studies.
Duration of illness at entry point during hospitalization and lactate dehydrogenase level in coronavirus disease 2019 pneumonia cases (n = 1000)
In the present study, we have documented a proportionate number of COVID-19 pneumonia cases with Doi <7 days, and many cases with Doi >15 days were having normal LDH level, while cases between 7 and 14 days of Doi were having abnormal or raised LDH level. Rational for this observation is not known and related to dynamic inflammatory pattern correlated with duration of illness. We have observed that as duration of illness between 7-14 days were having exaggerated inflammatory response due to evolution of COVID-19 pathology. Surprisingly, we have also noted that later during course of illness LDH level stabilised or decreased as inflammatory response restored with medical treatment or spontaneous homeostatic process. We have correlated LDH pattern with other inflammatory markers such as CRP, IL 6 and D dimer and documented that these markers raised parallel to LDH. As Doi in COVID-19 pneumonia cases increases, lung inflammation and tissue necrosis increase with worsening of hypoxia resulting in high LDH level. Liu etal. and Han etal. observed raised LDH with increased Doi due to more lung parenchymal involvement as disease duration progresses.
Association of bilevel-positive airway pressure use with lactate dehydrogenase level in coronavirus disease 2019 pneumonia cases (n = 1000)
In the present study, we have documented that IL-6 level has a positive correlation with requirement of BIPAP/NIV, high-flow nasal cannula (HFNC) oxygen supplementation, and invasive mechanical ventilation in a critical care setting. Henry etal. and Lv etal. documented a prognostic role of LDH in predicting severity and mentioned that increased LDH levels were associated with about 6-fold increase in odds of developing severe/critical disease. Wang etal. observed that elevated neutrophil count, D-dimer, BUN, creatinine, and LDH are predictors of poor outcome and maximum patients required mechanical ventilation in intensive care units and associated with mortality. Various researchers, Poggiali etal. and Han etal., documented similar observation in their studies. The present study revealed significantly higher LDH levels in severe cases requiring ventilatory support than in nonsevere patients suggesting that the LDH level may be a biomarker of disease severity and progression in patients with COVID-19 requiring aggressive interventions.
Association of oxygen saturation at entry point and lactate dehydrogenase level in coronavirus disease 2019 pneumonia cases (n = 1000)
In the present study, LDH level has a significant association with oxygen saturation in COVID-19 pneumonia cases. We have observed that a higher proportion of patients with elevated LDH have significant hypoxia at entry point and we have with anticoagulation and corticosteroid with protocolized interventions in intensive care units resulted in decreased hypoxia, inflammation, and LDH level during follow-up. Fang etal. and Li etal. observed similar findings. Xu etal. documented diffuse alveolar damage and hyaline membrane formation in autopsy studies of advanced COVID 19 patients. They have observed increased LDH in blood of these autopsied samples and came to the conclusion that the rise is LDH may be because of diffuse alveolar damage resulting from hypoxia induced cell necrosis and cytokine induced lung injury.
Association of bilevel-positive airway pressure/noninvasive ventilation initiation time at entry point and lactate dehydrogenase level coronavirus disease 2019 pneumonia cases (n = 600)
In the present study, timing of BIPAP/NIV requirement during course of COVID 19 pneumonia in a critical care setting has a significant association with LDH level. COVID-19 pneumonia cases received BIPAP/NIV at entry point has four fold raised LDH level in 110/70, 150/160, and 30/80 cases respectively (P<0.00001). Rational for similar observation would be these COVID-19 pneumonia cases required ventilatory support were advanced pneumonia cases with hypoxia resulting into anaerobic metabolism and LDH rise. We have documented that cases with and without ventilatory support requirement with hypoxia were having significantly different LDH titre. We have also observed as hypoxia corrected with ventilatory support, LDH level significantly drops and LDH titre can be utilised as marker of response to ventilatory support in correction of hypoxia. Poggiali et al, Sinelnikova EM et al. Yan L et al, Wu et al, Goyal et al, Booth et al, Li et al, and Garcia-Gordillo et al. observed findings collaborating with our study.
Other important observations in this study
Association of abnormal lactate dehydrogenase level at entry point (n = 680) and follow-up and its association with post-COVID lung fibrosis
We have documented that serial measurement of LDH during hospitalization irrespective of entry point abnormal level has a very well correlation with requirement of interventions in indoor and intensive care units such as HFNC, BIPAP/NIV, and invasive mechanical ventilation. We have observed the usefulness of LDH as markers for evaluating clinical severity and monitoring treatment response in COVID-19 pneumonia. We have documented that serial LDH titers will be helpful in assessing improvement or progression of disease. Interestingly, we have noted that persistent high level or rising trends of LDH indicate either nonspecific responses to hypoxia, tissue injury, and or necrosis. Thus, we especially mention that rising LDH trends indicate underlying radiological progression which is the earliest predictor of lung fibrosis in these cases. Wu etal., Chen etal., and Li etal. mentioned similar findings.
Association of normal lactate dehydrogenase level (n = 320) at entry point and follow-up and its association with post-COVID lung fibrosis
We have documented that normal LDH is a predictor of good clinical and radiological outcome and serial measurement of LDH during hospitalization irrespective of entry point level has a very well correlation with underlying lung pathology. We have observed that LDH rising trends would help in predicting exaggerated underlying lung parenchymal damage secondary to cytokine-induced lung necrosis and cytokine-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). These insults as necrosis or ALI/ARDS are considered an early marker of future lung fibrosis. We have observed that a small proportion of nonsevere patients developed into severe cases in the first 2 weeks after symptom onset. Therefore, we recommend that all health-care institutions should also pay close attention to mild patients, identify progressors early, and provide appropriate treatment to reduce mortality. Yan etal. in retrospective analysis in Wuhan, China, documented similar observations in their study.
Association of other variables and lactate dehydrogenase level in coronavirus disease 2019 pneumonia cases
In the present study, age of patients and gender of included cases has a significant association in COVID-19 cases with normal and abnormal LDH level. Huang et al., Duan et al. and Gao et al. documented similar observation in their study. In the present study, comorbidities such as diabetes mellitus, COPD, hypertension, IHD, and obesity have a significant association in COVID-19 cases with LDH level (P < 0.00001). Huang etal, Duan etal. and Gao etal. documented similar observation.
LDH is an easily available, sensitive and reliable, cost-effective, and universally acceptable inflammatory marker in COVID-19 pandemic. Correlating LDH with variables such as Doi, oxygenation status, and timing of BIPAP/NIV at entry point is important to have satisfactory treatment outcome.
LDH follow-up titer has significant associations in predicting progression of pneumonia which were easily picked up by rising LDH titers. LDH follow up titers have played a very crucial role in analysing response to treatment. Proportionate number of pneumonia cases with mild variety on CT thorax and normal initial LDH have progressed to critical illness which have been correlated with other inflammatory markers such as CRP and ferritin in intensive care settings.
Rising LDH titers in the 2nd week of illness indicates nosocomial bacterial infection and target therapy accordingly, and decreasing LDH titers has very well correlated with improved oxygenation status, excellent response to treatment, and decreased underlying inflammation. LDH sequential titers also guide in predicting risk of progression of COVID-19 pneumonia and post-COVID lung fibrosis irrespective of entry point titer.
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Conflicts of interest
There are no conflicts of interest.
2. Lippi G, Plebani M. The critical role of laboratory medicine during coronavirus disease 2019 (COVID-19) and other viral outbreaks. Clin Chem Lab Med 2020;58:1063–9.
3. Bohn MK, Lippi G, Horvath A, Sethi S, Koch D, Ferrari M, et al. Molecular, serological, and biochemical diagnosis and monitoring of COVID-19:IFCC taskforce evaluation of the latest evidence. Clin Chem Lab Med 2020;58:1037–52.
4. Cecconi M, Piovani D, Brunetta E, Aghemo A, Greco M, Ciccarelli M, et al. Early predictors of clinical deterioration in a cohort of 239 patients hospitalized for COVID-19 Infection in Lombardy, Italy. J Clin Med 2020;9:E1548.
5. Ferrari D, Motta A, Strollo M, Banfi G, Locatelli M. Routine blood tests as a potential diagnostic tool for COVID-19. Clin Chem Lab Med 2020;58:1095–9.
6. Adzerikho RD, Aksentsev SL, Okun' IM, Konev SV. Letter:Change in trypsin sensitivity during structural rearrangements in biological membranes. Biofizika 1975;20:942–4.
7. Henry BM, Aggarwal G, Wong J, Benoit S, Vikse J, Plebani M, et al. Lactate dehydrogenase levels predict coronavirus disease 2019 (COVID-19) severity and mortality:A pooled analysis. Am J Emerg Med 2020;38:1722–6.
8. Henry BM, de Oliveira MHS, Benoit S, Plebani M, Lippi G. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19):A meta-analysis. Clin Chem Lab Med 2020;58:1021–8.
9. Lippi G, Plebani M. Laboratory abnormalities in patients with COVID-2019 infection. Clin Chem Lab Med 2020;58:1131–4.
10. Zhang ZL, Hou YL, Li DT, Li FZ. Laboratory findings of COVID-19:A systematic review and meta-analysis. Scand J Clin Lab Invest 2020;80:441–7.
11. Huijgen HJ, Sanders GT, Koster RW, Vreeken J, Bossuyt PM. The clinical value of lactate dehydrogenase in serum:A quantitative review. Eur J Clin Chem Clin Biochem 1997;35:569–79.
12. Stankovic Stojanovic K, Lionnet F. Lactate dehydrogenase in sickle cell disease. Clin Chim Acta 2016;458:99–102.
13. Goldberg DM, Brown D. Biochemical tests in the diagnosis, classification, and management of patients with malignant lymphoma and leukemia. Clin Chim Acta 1987;169:1–76.
14. Jurisic V, Radenkovic S, Konjevic G. The actual role of LDH as tumor marker, biochemical and clinical aspects. Adv Exp Med Biol 2015;867:115–24.
15. Erez A, Shental O, Tchebiner JZ, Laufer-Perl M, Wasserman A, Sella T, et al. Diagnostic and prognostic value of very high serum lactate dehydrogenase in admitted medical patients. Isr Med Assoc J 2014;16:439–43.
16. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;382:1708–20.
17. Kermali M, Khalsa RK, Pillai K, Ismail Z, Harky A. The role of biomarkers in diagnosis of COVID-19 –A systematic review. Life Sci 2020;254:117788.
18. Shi J, Li Y, Zhou X, Zhang Q, Ye X, Wu Z, et al. Lactate dehydrogenase and susceptibility to deterioration of mild COVID-19 patients:a multicenter nested case-control study. BMC Med 2020;18:168.
19. Zhang JJY, Lee KS, Ang LW, Leo YS, Young BE. Risk factors for severe disease and efficacy of treatment in patients infected With COVID-19:A Systematic review, meta-analysis, and meta-regression analysis. Clin Infect Dis 2020;71:2199–206.
20. Aloisio E, Chibireva M, Serafini L, Pasqualetti S, Falvella FS, Dolci A, et al. Acomprehensive appraisal of laboratory biochemistry tests as major predictors of COVID-19 severity. Arch Pathol Lab Med 2020;144:1457–64.
21. Magdy AM, Saad MA, El Khateeb AF, Ahmed MI, Gamal El-Din DH. Comparative evaluation of semi-quantitative CT-severity scoring versus serum lactate dehydrogenase as prognostic biomarkers for disease severity and clinical outcome of COVID-19 patients. Egypt J Radiol Nucl Med 2021;52:114.
22. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497–506.
23. Payán-Pernía S, Gómez Pérez L, Remacha Sevilla ÁF, Sierra Gil J, Novelli Canales S. Absolute lymphocytes, ferritin, C-reactive protein, and lactate dehydrogenase predict early invasive ventilation in patients With COVID-19. Lab Med 2021;52:141–5.
24. Tao RJ, Luo XL, Xu W, Mao B, Dai RX, Li CW, et al. Viral infection in community acquired pneumonia patients with fever:A prospective observational study. J Thorac Dis 2018;10:4387–95.
25. Lv XT, Zhu YP, Cheng AG, Jin YX, Ding HB, Wang CY, et al. High serum lactate dehydrogenase and dyspnea:Positive predictors of adverse outcome in critical COVID-19 patients in Yichang. World J Clin Cases 2020;8:5535–46.
26. Tordjman M, Mekki A, Mali RD, Monnier H, Neveu S, Chassagnon G, et al. Determining extent of COVID-19 pneumonia on CT based on biological variables. Respir Med 2020;175:106206.
27. Boldt MJ, Bai TR. Utility of lactate dehydrogenase vs .Radiographic severity in the differential diagnosis of Pneumocystis carinii pneumonia. Chest 1997;111:1187–92.
28. Deng X, Liu B, Li J, Zhang J, Zhao Y, Xu K. Blood biochemical characteristics of patients with coronavirus disease 2019 (COVID-19):A systemic review and meta-analysis. Clin Chem Lab Med 2020;58:1172–81.
29. Xi X, Xu Y, Jiang L, Li A, Duan J, Du B, et al. Hospitalized adult patients with 2009 influenza A(H1N1) in Beijing, China:Risk factors for hospital mortality. BMC Infect Dis 2010;10:256.
30. Cho WH, Kim YS, Jeon DS, Kim JE, Kim KI, Seol HY, et al. Outcome of pandemic H1N1 pneumonia:Clinical and radiological findings for severity assessment. Korean J Intern Med 2011;26:160–7.
31. Liu CL, Lu YT, Peng MJ, Chen PJ, Lin RL, Wu CL, et al. Clinical and laboratory features of severe acute respiratory syndrome vis-a-vis onset of fever. Chest 2004;126:509–17.
32. Fang X, Mei Q, Yang T, Li L, Wang Y, Tong F, et al. Low-dose corticosteroid therapy does not delay viral clearance in patients with COVID-19. J Infect 2020;81:147–78.
33. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061–9.
34. Poggiali E, Zaino D, Immovilli P, Rovero L, Losi G, Dacrema A, et al. Lactate dehydrogenase and C-reactive protein as predictors of respiratory failure in CoVID-19 patients. Clin Chim Acta 2020;509:135–8.
35. Han Y, Zhang H, Mu S, Wei W, Jin C, Tong C, et al. Lactate dehydrogenase, an independent risk factor of severe COVID-19 patients:A retrospective and observational study. Aging (Albany NY) 2020;12:11245–58.
36. Li X, Xu S, Yu M, Wang K, Tao Y, Zhou Y, et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J Allergy Clin Immunol 2020;146:110–8.
37. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020;8:420–2.
38. Sinelnikova EM, Dvoretskova TV, Kagan ZS. Intermediate plateaux in kinetics of the reaction catalyzed by biodegradative L-threonine dehydratase from Escherichia coli
. Biokhimiia 1975;40:645–51.
39. Yan L, Zhang HT, Goncalves J, Xiao Y, Wang M, Guo Y, et al. An interpretable mortality prediction model for COVID-19 patients. Nat Mach Intell 2020;2:283–8.
40. Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020;180:934–43.
41. Goyal P, Choi JJ, Pinheiro LC, Schenck EJ, Chen R, Jabri A, et al. Clinical characteristics of Covid-19 in New York City. N Engl J Med 2020;382:2372–4.
42. Booth CM, Matukas LM, Tomlinson GA, Rachlis AR, Rose DB, Dwosh HA, et al. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA 2003;289:2801–9.
43. Li W, Lin F, Dai M, Chen L, Han D, Cui Y, et al. Early predictors for mechanical ventilation in COVID-19 patients. Ther Adv Respir Dis 2020;14:1753466620963017. doi:10.1177/1753466620963017.
44. Garcia-Gordillo JA, Camiro-Zúñiga A, Aguilar-Soto M, Cuenca D, Cadena-Fernández A, Khouri LS, et al. COVID-IRS:A novel predictive score for risk of invasive mechanical ventilation in patients with COVID-19. PLoS One 2021;16:e0248357.
45. Wu MY, Yao L, Wang Y, Zhu XY, Wang XF, Tang PJ, et al. Clinical evaluation of potential usefulness of serum lactate dehydrogenase (LDH) in 2019 novel coronavirus (COVID-19) pneumonia. Respir Res 2020;21:171.
46. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China:A descriptive study. Lancet 2020;395:507–13.
47. Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, et al. Coronavirus infections and immune responses. J Med Virol 2020;92:424–32.
48. Duan YN, Qin J. Pre- and posttreatment chest CT findings:2019 novel coronavirus (|y2019-nCoV) pneumonia. Radiology 2020;295:21.
49. Gao YD, Ding M, Dong X, Zhang JJ, Kursat Azkur A, Azkur D, et al. Risk factors for severe and critically ill COVID-19 patients:A review. Allergy 2021;76:428–55.