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ORIGINAL ARTICLE Table of Contents  
Ahead of print publication
C-reactive protein and lactate dehydrogenase in intensive care unit and nonintensive care unit COVID-19 patients – A retrospective study


1 Department of Biochemistry, Karnataka Institute of Medical Sciences, Hubballi, Karnataka, India
2 Department of General Medicine, Karnataka Institute of Medical Sciences, Hubballi, Karnataka, India

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Date of Submission25-Jan-2022
Date of Decision19-Mar-2022
Date of Acceptance25-May-2022
Date of Web Publication04-Aug-2022
 

  Abstract 


Background: Appropriate diagnostic markers play an important role in categorizing COVID-19 patients with respect to the severity of the disease. Aims and Objectives: The aim and objective of this study were to compare C-reactive protein (CRP) and lactate dehydrogenase (LDH) in intensive care unit (ICU) and non-ICU patients of COVID-19 disease. Materials and Methods: Data was collected from the COVID-19 laboratory (n = approximately 3700). The patients were divided into two groups: ICU and non-ICU. The levels of CRP and LDH were estimated by the microslide method based on an enzymatic heterogeneous sandwich immunoassay. Results: In the ICU group, patients above 50 years were four times in number compared to patients below 50 years. COVID-19 infection was twice more common in males than females. The mean CRP levels in the ICU group were higher compared to non-ICU group, and this difference was statistically significant. LDH was elevated significantly in ICU patients compared to non-ICU patients. Conclusion: The study concludes that patients aged above 50 years are more prone to develop severe COVID-19. Men are more susceptible to develop severe COVID-19. The most evident finding of this study is that among patients below 50 years, higher CRP levels can be used as an alarming marker in predicting severe COVID-19 disease. We suggest that LDH can be used as a marker to predict the severity of COVID-19 disease in all age groups. We also suggest that in patients above 50 years, it is better to use the combination of CRP and LDH in the assessment of severe COVID-19, rather than using CRP alone.

Keywords: COVID-19, C-reactive protein, lactate dehydrogenase


How to cite this URL:
Astagimath M, Aryapu R, Patil V, Doddamani S. C-reactive protein and lactate dehydrogenase in intensive care unit and nonintensive care unit COVID-19 patients – A retrospective study. APIK J Int Med [Epub ahead of print] [cited 2022 Oct 6]. Available from: https://www.ajim.in/preprintarticle.asp?id=353258





  Introduction Top


Severe acute respiratory syndrome-coronavirus-2 outbreak was reported in Wuhan, China in December 2019, later the entire world witnessed the pandemic.[1],[2] Clinically, the COVID-19 severity range from mild disease to life-threatening pneumonia in the form of acute respiratory distress syndrome (ARDS) which requires intensive care.[3] The majority of COVID-19 patients have mild flu-like symptoms, but a group of patients suffer from ARDS and multi-organ failure. Hence, it is of utmost importance to identify the predictors of severity of diseases, which can help us in appropriate categorization of these patients. The COVID-19 pandemic has presented a major challenge to the health-care system. One of the challenges faced by treating physicians is in identifying and categorizing the patients based on the severity of illness. In this, appropriate diagnostic markers play an important role. Hence, we planned to estimate the levels of C-reactive protein (CRP) and lactate dehydrogenase (LDH) in patients in nonintensive care unit (non-ICU) (mild disease) and ICU (severe disease). CRP is an acute inflammatory protein; whose concentration may increase up to 1000-fold at the sites of inflammation or infection. It is primarily synthesized in hepatocytes but also by macrophages, epithelial cells, smooth muscle cells, adipocytes, lymphocytes, and endothelial cells.[4] LDH is an enzyme present in the cytoplasm and is seen in almost all cells. It takes part in glucose metabolism and is involved in catalyzing the conversion of pyruvate to lactate.[5] LDH has five isoenzyme forms; LDH-3 is the major isoenzyme form present in the lung. Severe lung infections can result in tissue damage induced by the production of cytokine with the release of LDH in the bloodstream.[6] These laboratory biomarkers can play an important role in risk stratification and thus they are very much essential in a pandemic so that the distribution of resources can be carefully planned. The present study is based on an extensive survey of a large group of patients (approximately 3700 patients) and thus the results obtained from this study can be extended to the population at large.

Aims and objectives

The aim and objective of the study were to compare the levels of CRP and LDH in ICU and non-ICU patients with COVID-19 disease.


  Materials and Methods Top


This retrospective cross-sectional study included data collected from the COVID-19 laboratory of Karnataka Institute of Medical Sciences (KIMS), Hubballi, Karnataka, India, a tertiary care hospital between March 2020 and October 2020. This study includes the laboratory data of patients on admission who were admitted for COVID-19 treatment to KIMS hospital (approximately 3700 patients). CRP was measured in 3613 patients and LDH was measured in 3717 patients. The patients were divided into two groups: (1) those who were admitted to ICU (severe disease) and (2) those who were admitted to the wards (non-ICU) (mild disease). The patients were further divided into two groups of age <50 years and age >50 years as the government guidelines considered the patients aged above 50 years to be at a higher risk. COVID-19-positive newborns, mothers, pregnant ladies, and patients whose complete data were not available were excluded from the study. The levels of CRP and LDH were estimated using VITROS 250 chemistry system by the microslide method based on an enzymatic heterogeneous sandwich immunoassay. Ethical committee permission was obtained from the Institutional Ethical Committee. Statistical analysis was done using the SPSS and Medcalc software (IBM SPSS statistics ver.21).


  Results Top


In the ICU group, patients above 50 years were four times in number compared to patients below 50 years. COVID-19 infection was twice more common in males than females. The mean CRP levels in the ICU group were higher compared to non-ICU group, and this difference was statistically significant (P = 0.0163). Among patients above 50 years, the difference in mean CRP levels was not statistically significant (P = 0.5303) in ICU and non-ICU groups, whereas there was a significant difference in mean CRP levels among patients below 50 years (P = 0.0081) in ICU and non-ICU group. LDH was elevated significantly in ICU patients compared to non-ICU patients (P < 0.0001).


  Discussion Top


In this retrospective study of CRP and LDH in COVID-19 patients, it is quite evident that, in severe COVID-19 (ICU group), patients above 50 years were four-fold more [Table 1] and [Table 2]. This suggests that patients above 50 years are at higher risk of developing severe disease. In our previous research, we found age above 65 years is a risk factor for developing severe COVID-19 disease.[7] This finding is in line with the findings from the study conducted by Geng et al. who concluded that older age is a risk factor for developing severe COVID-19 disease.[8] In the older age group, the severity of the illness can be attributed to the higher association of comorbidities, and also because with an increase in age, there is a decline in the immune function also known as immune senescence, which causes slowing of the viral alert signals, which may result in greater viral replication.[9]
Table 1: Descriptive parameters in intensive care unit and nonintensive care unit patients in the different age groups

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Table 2: Descriptive parameters in intensive care unit and nonintensive care unit patients with respect to gender

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It is found that irrespective of patients admitted to ICU or non-ICU, the preponderance of developing severe COVID-19 was two-fold in males compared to females. Similar findings were also reported by Jin et al. which state that while men and women have the same prevalence, men with COVID-19 are more at risk for developing severe illness and death, independent of age.[10] The cause for males developing severe disease could be due to sex hormones and increased expression of angiotensin-converting enzyme-2 in men and the other possibilities might be due to associated behavioral causes such as smoking, which is more commonly seen in males compared to females.[11]

Overall CRP levels were increased significantly (P = 0.0163) in ICU patients compared to non-ICU patients. Among patients below 50 years, there was a significant difference in mean CRP levels in ICU and non-ICU groups (P = 0.0081) [Table 3] which suggests that higher levels of CRP can be an alarming marker in predicting severe COVID-19 in this age group. Whereas in patients above 50 years, the difference in mean CRP levels was not statistically significant (P = 0.5303) in ICU and non-ICU groups, which suggests that the increase in CRP may be influenced by age. A study conducted by TangY states that the levels of CRP tend to increase with age and this could be due to age-related diseases.[12] Thus, in patients above 50 years, the CRP levels may not reflect the severity of the disease proportionately. The findings from this study are similar to a study conducted by Mueller et al. on 100 patients shows rising CRP predicts subsequent respiratory deterioration in COVID-19 and may suggest an insight and a potential role for targeted immune modulation in the COVID-19 patients early during hospitalization.[13] Another similar study conducted by Lobo et al. on 313 patients with COVID-19 found that elevated levels of CRP during admission lead to poor outcomes and also increase the risk of organ failure and death.[14] The increased level of CRP may be due to the increased production of inflammatory cytokines in patients suffering from severe COVID-19. When the immune system becomes hyperactive, it may cause damage to the lung tissue. Thus, the production of CRP is induced by inflammatory cytokines and also by the destruction of tissue in patients with severe COVID-19.
Table 3: Comparison of laboratory parameters among intensive care unit and nonintensive care unit patients

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Serum LDH was increased significantly in ICU patients compared to non-ICU patients (P < 0.0001) [Table 3]. The similar statistically significant difference was noted in males (P < 0.0001), females (P = 0.0713), patients above 50 years (P = 0.0003), and below 50 years (P = 0.0004). This finding suggests that irrespective of age and gender, LDH is a good indicator of the severity of the disease. Wu et al. conducted a study on 87 patients that showed significant differences in LDH levels between nonsevere and severe groups (P < 0.05) and it was also demonstrated that an increase or decrease in LDH was indicative of radiographic progress or improvement.[15] Han et al. did a study on 107 COVID-19 patients and they concluded that LDH can act as a strong predictor for early recognition of lung injury and severe disease.[5] LDH leads to an increase in levels of lactate, thus causing enhancement of immune-suppressive cells, which include dendritic cells and macrophages, and also leads to inhibition of cytolytic cells. Cytotoxic T-cell antigens and antibodies have a role in the enhancement of T-cell activity and proliferation. In a retrospective analysis of cytotoxic T-cell antigen and antibody, it was shown that an increase in levels of LDH indicates poor outcomes, which suggests the inhibitory effect of LDH on cytotoxic T-cell antigens.[16]

Limitations

The COVID-19 patients in home isolation were excluded from this study.

Scope for further study

Serial follow-up of laboratory parameters along with clinical characteristics of patients can give a better insight to understand the disease process and to assess the prognostic use of the laboratory parameters.


  Conclusion Top


The study concludes that patients aged above 50 years are more prone to develop severe COVID-19. Men are more susceptible to develop severe COVID-19. The most evident finding of this study is that among patients below 50 years, higher CRP levels can be used as an alarming marker in predicting severe COVID-19 disease. To the best of the authors' knowledge, this is the first study to show this finding. We suggest that LDH can be used as a marker to predict the severity of COVID-19 disease in all age groups. We also suggest that in patients above 50 years, it is better to use the combination of CRP and LDH in the assessment of severe COVID-19, rather than using CRP alone.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020;382:727-33.  Back to cited text no. 1
    
2.
Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270-3.  Back to cited text no. 2
    
3.
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020;395:1054-62.  Back to cited text no. 3
    
4.
Sproston NR, Ashworth JJ. Role of C-reactive protein at sites of inflammation and infection. Front Immunol 2018;9:1-11.  Back to cited text no. 4
    
5.
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.  Back to cited text no. 5
    
6.
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.  Back to cited text no. 6
    
7.
Astagimath MN, Raviraja A. Suman Doddamani. J Stress Physiol Biochem 2021;17:105-12.  Back to cited text no. 7
    
8.
Geng MJ, Wang LP, Ren X, Yu JX, Chang ZR, Zheng CJ, et al. Risk factors for developing severe COVID-19 in China: An analysis of disease surveillance data. Infect Dis Poverty 2021;10:48.  Back to cited text no. 8
    
9.
Mahase E. COVID-19: Why are age and obesity risk factors for serious disease? BMJ 2020;371:m4130.  Back to cited text no. 9
    
10.
Jin JM, Bai P, He W, Wu F, Liu XF, Han DM, et al. Gender differences in patients with COVID-19: Focus on severity and mortality. Front Public Health 2020;8:152.  Back to cited text no. 10
    
11.
Bwire GM. Coronavirus: Why men are more vulnerable to COVID-19 than women? SN Compr Clin Med 2020;2:874-6.  Back to cited text no. 11
    
12.
Tang Y, Fung E, Xu A, Lan HY. C-reactive protein and ageing. Clin Exp Pharmacol Physiol 2017;44:9-14.  Back to cited text no. 12
    
13.
Mueller AA, Tamura T, Crowley CP, DeGrado JR, Haider H, Jezmir JL, et al. Inflammatory biomarker trends predict respiratory decline in COVID-19 patients. Cell Rep Med 2020;1:100144.  Back to cited text no. 13
    
14.
Lobo SM, Lobo FR, Bota DP, Lopes-Ferreira F, Soliman HM, Mélot C, et al. C-reactive protein levels correlate with mortality and organ failure in critically ill patients. Chest 2003;123:2043-9.  Back to cited text no. 14
    
15.
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.  Back to cited text no. 15
    
16.
Dick J, Lang N, Slynko A, Kopp-Schneider A, Schulz C, Dimitrakopoulou-Strauss A, et al. Use of LDH and autoimmune side effects to predict response to ipilimumab treatment. Immunotherapy 2016;8:1033-44.  Back to cited text no. 16
    

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Correspondence Address:
Suman Doddamani,
Department of Biochemistry, Karnataka Institute of Medical Sciences, Vidyanagar, Hubballi - 580 021, Karnataka
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajim.ajim_18_22




 
 
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    -  Aryapu R
    -  Patil V
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