|Year : 2021 | Volume
| Issue : 1 | Page : 27-30
A review article on biochemical predictors of COVID-19 infection
Ria Lawrence, Amal Johnson, Raghupathi Narasimhan
Department of Respiratory Medicine, Apollo Main Hospital, Chennai, Tamil Nadu, India
|Date of Submission||30-Apr-2021|
|Date of Decision||01-May-2021|
|Date of Acceptance||31-May-2021|
|Date of Web Publication||22-Sep-2021|
Department of Respiratory Medicine, Apollo Main Hospital, Greams Lane, Chennai - 600 006, Tamil Nadu
Source of Support: None, Conflict of Interest: None
The coronavirus disease 2019 (COVID-19) pandemic is a scientific, medical, and social challenge. The complexity of the severe acute respiratory syndrome coronavirus 2 is centered on the unpredictable clinical course of the disease that can rapidly develop causing severe and deadly complications. The identification of effective laboratory biomarkers and being able to classify patients based on their risk is imperative in guaranteeing appropriate treatment. The analysis of recently published studies highlights the role of systemic vasculitis and cytokine-mediated coagulation disorders as the principal actors of multi-organ failure in patients with severe COVID-19 complications. In this review article, we will be discussing the role of biomarkers in the management of COVID-19 infection.
Keywords: Biomarkers, COVID, D-dimer, Il6, predictors
|How to cite this article:|
Lawrence R, Johnson A, Narasimhan R. A review article on biochemical predictors of COVID-19 infection. J Assoc Pulmonologist Tamilnadu 2021;4:27-30
|How to cite this URL:|
Lawrence R, Johnson A, Narasimhan R. A review article on biochemical predictors of COVID-19 infection. J Assoc Pulmonologist Tamilnadu [serial online] 2021 [cited 2022 Jan 28];4:27-30. Available from: http://www.japt.com/text.asp?2021/4/1/27/326409
| Introduction|| |
The coronavirus disease 2019 (COVID-19) has been declared as a pandemic on March 12, 2020. The pathogen has been identified as a novel enveloped RNA betacoronavirus that is currently known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Like severe acute respiratory syndrome (SARS) coronavirus (CoV) and Middle East respiratory syndrome (MERS) coronavirus, SARS-CoV-2 is a highly pathogenic coronavirus. The virus has high transmission capability as well as high morbidity and mortality. By April 22, 2020, the acute respiratory disease has affected more than 200 countries worldwide. However, little is still known about the factors that lead to death by this virus.
| Etiopathogenesis|| |
The SARS-CoV-2 is a positive-stranded RNA virus belonging to the genus Betacoronavirus with the presence of spike glycoproteins on the envelope. Other than SARS-CoV-2, there are six types of humans coronaviruses have been identified, namely, HCoV-229E, HCoV-OC43, SARS-CoV, HCoV-NL63, HCoV-HKU1, and MERS-CoV. Phylogenetic analysis revealed that the SARS-CoV-2 is closely related, with 88%–89% similarity, to two bat-derived SARS such as coronaviruses, bat-SL-CoVZC45, and bat-SL-CoVZXC21, but it is more distant from SARS-CoV, with about 79% similarity, and MERS-CoV, with about 50% similarity. The SARS-CoV-2 has an envelope; its particles are round or elliptic and often polymorphic form and a diameter of 60 nm to 140 nm.
The inhaled virus SARS-CoV-2 binds to epithelial cells in the nasal cavity and starts replicating. Angiotensin-converting enzyme 2 (ACE2) is the main receptor for both SARS-CoV-2 and SARS-CoV. In vitro data with SARS-CoV indicate that the ciliated cells are primary cells infected in the conducting airways. There is local propagation of the virus but a limited innate immune response. At this stage, the virus can be detected by nasal swabs. Although the viral burden may be low, these individuals are infectious. The virus propagates and migrates down the respiratory tract along the conducting airways, and a more robust innate immune response is triggered. Nasal swabs or sputum should yield the virus (SARS-CoV-2) as well as early markers of the innate immune response. By this time, the disease COVID-19 will clinically manifest. The level of CXCL10 (or some other innate response cytokine) may be predictive of the subsequent clinical course. Viral infected epithelial cells are a major source of beta and lambda interferon. CXCL10 is an interferon responsive gene that has an excellent signal-to-noise ratio in the alveolar type II cell response to both SARS-CoV and influenza. CXCL10 has also been reported to be useful as disease marker in SARS. Determining the host innate immune response might improve predictions on the subsequent course of the disease and the need for more aggressive monitoring.
| Discussion|| |
Lactate dehydrogenase (LDH) is an enzyme implicated in the conversion of lactate to pyruvate in the cells of most body tissues and increased following tissue breakdown. Consequently, elevated serum LDH is present in numerous clinical conditions, such as hemolysis, cancer, severe infections and sepsis, liver diseases, hematologic malignancies, and many others. Nowadays, there is much evidence suggesting that serum LDH levels serve as a nonspecific indicator of cellular death in many diseases. In a study conducted by Mei-Ying Wu et al. and Xingtong Dong et al., it was found that LDH is a reliable marker in predicting COVID severity.
Serum LDH was validated for its potential usefulness as markers for evaluating clinical severity and monitoring treatment response in COVID-19 pneumonia. It was demonstrated that increase or decrease of LDH was indicative of radiographic progress or improvement. An increase in LDH by 62.5 U/L has an acceptable sensitivity and high specificity for a significantly higher probability of disease progression when chest computed tomography (CT) scan was employed to confirm the prediction. In support, during the whole observation period, normalization of the serum LDH titer was consistently accurate in predicting treatment success in the patients.
Interleukin-6 (IL-6) is a pleiotropic cytokine produced in response to tissue damage and infections. Multiple cell types including fibroblasts, keratinocytes, mesangial cells, vascular endothelial cells, mast cells, macrophages, dendritic cells, and T and B cells are associated with the production of this cytokine. After targeting its specific receptor, IL-6 starts a cascade of signaling events mainly associated with the Janus kinase (JAK)/Signal transducer and activator of transcription 3 (STAT3) activation pathway promoting the transcription of multiple downstream genes associated with cellular signaling processes, including cytokines, receptors, adaptor proteins, and protein kinases. IL-6 is one of the main mediators of inflammatory and immune response initiated by infection or injury and increased levels of IL-6 are found in more than one half of the patients with COVID-19. Levels of IL-6 seem to be associated with inflammatory response, respiratory failure, needing for mechanical ventilation, and/or intubation and mortality in COVID-19 patients. In various studies like Tobias Herold et al., Coomes et al., it has been seen that the IL6 values correlate with the clinical severity of the disease.
The elevation of IL-6 has been previously demonstrated in the inflammatory state for multiple conditions. The pathophysiological hallmark of COVID-19 is the severe inflammation and chemokine storm, which explains the elevation of IL-6. The importance of identifying this elevated biomarker also helps in the potential use of antibody against IL-6 such as tocilizumab. IL-6 levels at hospital admission seem to be a good prognosticator for the combined endpoint progression to severe disease and/or in-hospital mortality, and it seems to be the best prognosticator for negative outcomes. The risk of respiratory failure for patients with IL-6 levels of ≥80 pg/ml was 22 times higher compared to patients with lower IL-6 levels [Table 1].
Serum ferritin is also a well-known inflammatory marker, but it is unclear whether serum ferritin reflects or causes inflammation, or whether it is involved in an inflammatory cycle. We argue here that serum ferritin arises from damaged cells, and is thus a marker of cellular damage.
The mechanisms responsible for the association of hyperferritinemia and disease severity in patients with COVID-19 are unclear, but there are several possibilities for this phenomenon:
- Proinflammatory cytokines such as IL-lβ, tumor necrosis factor-α (TNF-α), and IL-6 may increase ferritin synthesis. Hence, we speculated that SARS-CoV-2-induced production of proinflammatory cytokines (i.e., IL-6, TNF-α), which are known to be elevated in COVID-19, might promote ferritin synthesis early in inflammation
- The cellular damage derived from inflammation can promote the leakage of intracellular ferritin, thus elevating serum ferritin
- In acidosis, the microvascular environment and increased production of reactive oxygen species might liberate iron from ferritin, and it is this unliganded iron that can participate in Haber-Weiss and Fenton reactions, creating hydroxyl radicals, causing further cellular damage, and worsening tissue injury, thus causing a vicious cycle of inflammation. Similarly, one study found that the assembly of MERS coronavirus nanoparticles is related to chaperone-mediated ferritin. However, further investigations are needed to confirm the role of serum ferritin levels in the pathogenesis of COVID-19. The high level of serum ferritin is an independent risk factor for the severity of COVID-19. Assessing serum ferritin levels during hospitalization may be important to recognize high-risk individuals with COVID-19.
D-dimers are one of the fragments produced when plasmin cleaves fibrin to break down the clots. The assays are routinely used as part of a diagnostic algorithm to exclude the diagnosis of thrombosis. However, any pathologic or nonpathological process that increases fibrin production or breakdown also increases plasma D-dimer levels.
Several studies have shown that D-dimer levels are associated with the severity of community-acquired pneumonia and clinical outcome. There is a significant correlation between D-dimer levels and disease severity stratified by the area of affected lungs on chest CT, oxygenation index, as well as clinical staging according to the interim guideline. In addition, a higher percentage of D-dimer elevation was seen in the recent studies than previously reported. This may be due to the higher percentage of severe/critically ill cases referred to the hospital, which is another demonstration of the correlation between D-dimer level and disease severity. This suggests that the assay may be used early as a marker of severity before chest CT scans or as a complement to CT and clinical staging.
The elevated levels of C-reactive protein (CRP) might be linked to the overproduction of inflammatory cytokines in severe patients with COVID-19. Cytokines fight against the microbes but when the immune system becomes hyperactive, it can damage lung tissue. Thus, CRP production is induced by inflammatory cytokines and by tissue destruction in patients with COVID-19. The elevated level of CRP may be a valuable early marker in predicting the possibility of disease progression in nonsevere patients with COVID-19, which can help health workers to identify those patients an early stage for early treatment. Besides, COVID-19 patients with elevated levels of CRP need close monitoring and treatment even though they did not develop symptoms to meet the criteria for the severe disease course.
Patients who died of COVID-19 infections, displayed significantly higher CRP concentrations compared to the survivors. Sensitivity analysis by the exclusion of a study each time demonstrated significant associations of CRP with mortality, further strengthen the observation of the present analysis. CRP is an acute-phase protein responsible for the clearance of pathogens through the complement system and enhanced phagocytosis. The most common complications in nonsurvivors COVID-19 infected patients include acute respiratory distress syndrome, acute cardiac injury, acute kidney injury, shock, disseminated intravascular coagulation, and significant alterations in CRP level have been observed in these participants. A positive correlation between CRP concentrations with the lung lesion in COVID-19 infected patients has been demonstrated. Furthermore, the induction of acute kidney damage and the extent of the cardiac injury have been directly linked with the CRP concentrations. Possibly for clearance of viral infections, the immune system responded more vigorously by producing various immune molecules, and production of CRP beyond the threshold limit may lead to dysfunction of various organs in COVID-19 infected patients.
The synthesis of Procalcitonin (PCT) can be increased as a result of endotoxins and/or cytokines (e. g., IL-6, TNF-α, and IL-1b). The extra-thyroid synthesis of PCT has been found to occur in the liver, pancreas, kidney, lung, intestine, and within leukocytes. However, the synthesis of PCT has been shown to be suppressed within these tissues in the absence of bacterial infection. In contrast, cytokines, such as interferon (INF)-γ, which are released following viral infection, lead to downregulation of PCT, thus highlighting another advantage of PCT assays. PCT levels are either unmodified or only moderately increased in the systemic inflammatory response to viral or to noninfectious stimuli (nonviral infections). Therefore, PCT values were more discriminative than white blood cell count and CRP in distinguishing a bacterial infection from another inflammatory process. As for COVID-19 patients, more severe cases showed a more marked increase of PCT compared with nonsevere cases. A slight increase (much <0.5 ng/mL) in PCT levels is an important indicator to distinguish between SARS-CoV-2-positive and SARS-CoV-2-negative patients, and increased PCT values have been associated with a nearly fivefold higher risk of severe SARS-CoV-2 infection (odds ratio: 4.76; 95% confidence interval: 2.74–8.29). PCT value remains within reference ranges in patients with noncomplicated SARS-CoV-2 infection; any substantial increase reflects bacterial coinfection and the development of a severe form of disease and a more complicated clinical picture.
| Conclusion|| |
The work to date suggests that there is clear evidence of how the levels of biomarkers may change according to the severity of COVID-19 infection. This can be used as an adjunct in clinical practice to guide treatment and admission to the intensive care unit. Serial monitoring of biomarkers in moderate to critically ill COVID-19 pneumonia patients will help in assessing the clinical course and prognostic outcomes of the disease. Physicians have to correlate the serum biomarkers with clinical and radiological features in the management of COVID patients.
Thanks to the Department of Biochemistry, Apollo Hospitals, Chennai.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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