Introduction
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.[ 1 ] 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,[ 11 ] in hemolytic anemia,[ 12 ] in megaloblastic anemia, Hodgkin disease and non-Hodgkin lymphoma, and leukemias.[ 13 ] 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.[ 14 ] 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.[ 17 ] 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[ 20 ] 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.[ 20 ]
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
Data source
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.
Ethical approval
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 ] Figure 1: Flow of the study
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.
Statistical analysis
The statistical analysis was done by using Chi-square test in R-3.4 software. Significant values of χ 2 P value was considered significant if it was below 0.05 and highly significant in case if it was <0.001.
Results: Covariates
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 ].
Table 1: Other variables and lactate dehydrogenase level in coronavirus disease 2019 pneumonia cases (n =1000)
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 ].
Table 2: Duration of illness at entry point during hospitalization and lactate dehydrogenase level in coronavirus disease 2019 pneumonia cases (n =1000)
Table 3: Association of computed tomography severity (at entry point) and lactate dehydrogenase in coronavirus disease 2019 cases (n =1000)
Table 4: Oxygen saturation at entry point and lactate dehydrogenase level in coronavirus disease 2019 pneumonia cases (n =1000)
Table 5: Association of bilevel-positive airway pressure use with lactate dehydrogenase level in coronavirus disease 2019 pneumonia cases (n =1000)
Table 6: Bilevel-positive airway pressure/noninvasive ventilation initiation time at entry point and lactate dehydrogenase level coronavirus disease 2019 pneumonia cases (n =600)
Table 7: Abnormal lactate dehydrogenase level at entry point (n =680) and follow-up and its association with post-COVID lung fibrosis
Table 8: Normal lactate dehydrogenase level (n =320) at entry point and follow-up and its association with post-COVID lung fibrosis
Discussion
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. ,[ 21 ] Huang et al. ,[ 22 ] Salvador et al. ,[ 23 ] Tao et al. ,[ 24 ] Lv XT et al. ,[ 25 ] Tordjman et al. ,[ 26 ] Boldt et al. ,[ 27 ] Deng et al. ,[ 28 ] Xi et al. ,[ 29 ] and Cho et al .[ 30 ] 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 et al .[ 31 ] and Han et al .[ 32 ] 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 et al .[ 7 ] and Lv et al .[ 25 ] 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 et al .[ 33 ] 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 et al .[ 34 ] and Han et al .,[ 35 ] 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 et al .[ 36 ] and Li et al .[ 36 ] observed similar findings. Xu et al .[ 37 ] 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 ,[ 34 ] Sinelnikova EM et al .[ 38 ] Yan L et al ,[ 39 ] Wu et al ,[ 40 ] Goyal et al ,[ 41 ] Booth et al ,[ 42 ] Li et al ,[ 43 ] and Garcia-Gordillo et al .[ 44 ] 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 et al .,[ 45 ] Chen et al .,[ 46 ] and Li et al .[ 47 ] 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 et al .[ 39 ] 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 .[ 22 ] , Duan et al .[ 48 ] and Gao et al .[ 49 ] 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 et al ,[ 22 ] Duan et al .[ 48 ] and Gao et al .[ 49 ] documented similar observation.
Conclusions
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.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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