|Year : 2023 | Volume
| Issue : 1 | Page : 37-45
Role of clinical laboratory investigations in severe acute respiratory syndrome Corona Virus 2 infection: Lesson learnt for future
Sathishbabu Murugaiyan1, H Nandeesha1, J Pradeep Kumar2, S Balachandar3, S Hariprasad4
1 Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Karaikal, Puducherry, India
2 Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
3 Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research, Karaikal, Puducherry, India
4 Department of Medicine, Employees' State Insurance Corporation Medical College and Hospital, Chennai, Tamil Nadu, India
|Date of Submission||01-Jul-2022|
|Date of Decision||01-Nov-2022|
|Date of Acceptance||15-Nov-2022|
|Date of Web Publication||23-Feb-2023|
Dr. Sathishbabu Murugaiyan
Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Karaikal, Puducherry
Source of Support: None, Conflict of Interest: None
Zoonotic infection, severe acute respiratory syndrome coronavirus 2 causes several million deaths worldwide from its pandemic origin in China to date due to lack of proper diagnosis and treatment. Clinical laboratory investigations in biochemistry and pathology can be markers for sepsis, cardiovascular and hepatorenal impairment and genetic variations in angiotensin-converting enzyme as well as in ABO blood group play a vital role in predicting severity and prognosis in patients with comorbidities. In this minireview, the article will discuss the beneficial role of clinical laboratory markers in the management of coronavirus diseases 2019 and the possible factors which contribute to variations in laboratory results that may require attention during clinical management.
Keywords: Coronavirus diseases 2019, laboratory, markers, severe acute respiratory syndrome coronavirus 2
|How to cite this article:|
Murugaiyan S, Nandeesha H, Kumar J P, Balachandar S, Hariprasad S. Role of clinical laboratory investigations in severe acute respiratory syndrome Corona Virus 2 infection: Lesson learnt for future. J Med Evid 2023;4:37-45
|How to cite this URL:|
Murugaiyan S, Nandeesha H, Kumar J P, Balachandar S, Hariprasad S. Role of clinical laboratory investigations in severe acute respiratory syndrome Corona Virus 2 infection: Lesson learnt for future. J Med Evid [serial online] 2023 [cited 2023 Jun 7];4:37-45. Available from: http://www.journaljme.org/text.asp?2023/4/1/37/370396
| Introduction|| |
In the era of coronavirus disease 2019 (COVID-19), clinical laboratory services are being used extensively to identify comorbidity and in risk stratification for admission who need critical care and observation. Enormous difficulties have been observed in the management of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by most of developing countries like India., Laboratory markers like sphingolipid and active form of acid ceramidase levels are beneficial in the diagnosis of asymptomatic infections. Still, the infection is reported in several parts of the globe, with several deaths. Whether coronavirus will become endemic disease or may be associated with human depends on interactions between the immune status of the population and the immune escaping capacity of the virus, which is uncertain to predict. Hence, in this uncertain situation, it is worthwhile to discuss various Clinical laboratory investigations used as biomarkers recourses in the management of COVID-19 for future pandemics, if any. Moreover, earlier literatures indicate variation in laboratory results due to pre-analytical, analytical and post-analytical errors may jeopardise patient care, which needs attention amongst clinician and health-care workers., Hence, in this minireview, the effort was made to give the recent updated answer to the following questions with existing laboratory knowledge from literatures and our experience during COVID-19 and to provide better health care in future.
- What are the biochemical and pathology investigations useful during SARS-CoV-2 infection?
- What are the factors that could affect those parameters in the interpretation of laboratory reports?
In India, index case was reported in Kerala on 27 January 2020, a young female travelled from Wuhan city and the first victim of coronavirus was reported in Karnataka with a travel history from Saudi Arabia., Clinical features for the diagnosis of COVID-19 initial stage of the pandemic were confusing, with many presentations with a median incubation period of 5.1 days, about 17.9–33.3 are asymptomatic. Symptoms include fever, cough and difficulty in breathing, acute respiratory failure, shock and multiorgan failure. Some present less frequent symptoms such as sore throat, anosmia, dysgeusia, anorexia, nausea, malaise, myalgia and diarrhoea., In [Table 1], clinical features and tests required for laboratory investigations have been depicted. Studies documents that Systemic infections and comorbidities impair the functioning of the cardiovascular and hepatorenal system found to have an increased risk of mortality and which can be assessed earlier by various clinical laboratory markers., Systemic infections and other comorbidities present earlier or acquired during SARS-CoV2 infection impairs the functioning of the cardiovascular and hepatorenal systems found to have an increased risk of mortality and which can be assessed earlier by various clinical laboratory markers. The logical approach is required in a negative real-time polymerase chain reaction (RT-PCR) with abnormal laboratory investigations with its clinical correlation of SARS-CoV2 infection. Along with confirmatory microbiological investigation, nasal swab and RT-PCR test, haemogram, coagulation profile, inflammatory markers and other biochemical investigation tests largely requested during the COVID-19 pandemic has value.
|Table 1: Laboratory investigation recommended in different clinical features in severe acute respiratory syndrome coronavirus 2 management|
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| Overall Pathophysiology of the Severe Acute Respiratory Syndrome Corona Virus 2 Infection|| |
The SARS corona virus-2 belongs to the Coronaviriade family and is the cause of the recent pandemic with acute severe respiratory illness. The structure of coronavirus is a spherical, single-stranded ribonucleic acid (RNA) virus. Coronavirus has four structural proteins, and their functions are as below:
- The spike (S) is essential for host attachment and invasion
- Membrane (M) promotes viral assembly
- Envelop (E) is essential for assembly and budding
- The nucleocapsid is important for immune responses.
What are the sources of infection and transmission for severe acute respiratory syndrome coronavirus 2
Genetically similar viruses exist in rhinolophid bats and pangolins, zoonotic transmission and human-to-human transmission via oral and respiratory aerosols and droplets with the virus are the targets for intervention to avoid the spread. The WHO Guidelines recommends avoiding raw and undercooked animal and animal product consumption with other safety guidelines. Several strains of coronavirus are known to affect humans, but the new variant OMICRON B7 is a concern. Older strains such as human CoV 229E (HCoV-229E), HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV and MERS-CoV until 2020 affects human.,, In general, a clear understanding of pathophysiology can help to analyse the role of various laboratory markers, which will be discussed later.
Virus entry and multiplication
Angiotensin-converting enzymes receptor in the airways system (ACE 2 receptor) and type 2 transmembrane serine proteases (TMPRSS2) receptor expression is more in lung at type 2 Pneumocytes also in other organs such as the heart, ileum, kidney and bladder. The spike protein (S) of the virus binds to the host cell at ACE receptor in the airways system (ACE-2). With the help of serine proteases activity (TMPRSS2) in host cells, the uptake of the viral particles takes place through an enzyme-mediated cleavage system. Once the viral genetic material (RNA) enters the cytoplasm, it undergoes replication and the enzyme RNA-dependent RNA polymerase promotes the transcription of viral RNA and followed by the synthesis of a new protein; next step is an integration of the virus with the cellular Endoplasmic reticulum (ER), these viral buds are enclosed-on ER membrane and further transported to the lumen and then to Golgi bodies and finally released into extracellular space. Now, the new viral nucleocapsid is ready to spread in the community from the alveolar cells via droplets. Viral RNA →Host cells →Replication →Transcription →Translation →Endoplasmic membrane →Golgi bodies →Extracellular space →Transmission of disease., In addition to alveolar cells, SARS-CoV2 infects capillary endothelial cells, causing an inflammatory response with endothelialitis along with infiltrations of immune cells and the release of various cytokines [Table 2], affecting lung diffusion leading to oedema and hypoxia.,,,,,
| Cytokine Storm, an Immune-Induced Damage in Severe Acute Respiratory Syndrome Corona Virus 2 Infection|| |
Cytokine storm (CS) is the most unwanted event in the SARS-CoV 2 infection which can affect multiple organs and could be fatal. To the best of our knowledge, the definition of cytokine storm is yet to be established. The term cytokine storm has been coined and used since the year 1993 as a post transplant adverse reaction after stem cell therapy and also in several other conditions like sepsis, autoinflammatory diseases, haemophagocytic lymphohistiocytosis, H5N1, Variola infection etc., The term cytokine storm once again becomes popular during recent COVID-19 pandemic with unexpected death. The reason could be due to unavailability of effective treatment protocol, age factor and comorbities., Literature suggests that in CS syndrome, multiple organs are affected with exaggerated immune response primarily due to dysregulated cytokine metabolism.
Cytokine storm occurs in two stages in the body
At the early stage, there is weak interferon (IFN) response which is milder like haemophagocytic lymphohistiocytosis. However, during 2nd stage, there is hypersecretion of inflammatory cytokines, which is considered as an exaggerated response of the host cell to infection to compensate for earlier stage delay of type I and III IFNs response, including IFN α/ß. CS is positively associated with the severe form of COVID-19 infection and death due to acute respiratory distress syndrome or multiple-organ dysfunction, mediated by immunoinflammatory pathways involving interleukins (ILs) primarily involved in the dissolving of several viruses or inflammatory responses, as depicted in [Figure 1].,,, Mutation of the gene causing haemophagocytic lymphohistiocytosis and malignancy conditions is also associated with CS, and the mechanism compared with non-COVID is different. Although, newer evidence suggests tissue damage in the lung not solely on proinflammatory pathways but also due to hyperstimulation of glutamate receptors in the lung and immune cells called excitoimmunotoxicity. The clue for early identification of this dangerous condition is important for the clinician for critical management. IL6 is used as a marker to identify the CS in critically ill patients along with other parameters such as C-reactive protein (CRP), erythrocyte sedimentation rate and ferritin levels. Several cytokines are also elevated in ICU admitted than in non-ICU COVID patients.,,
|Figure 1: Overall immune inflammatory response to release interleukins after SARS-CoV-2 infection causing release of ILs from macrophages which stimulate inflammatory cycle to cause cell injury and endothelial leaks. SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2, IL: Interleukin|
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| Various Laboratory Biomarkers in Severe Acute Respiratory Syndrome Corona Virus 2 Infection|| |
C-reactive protein in corona virus diseases 2019
Plasma CRP, a non-specific marker that is increased in several inflammatory conditions and can predict severity in COVID-19 patients in the early course of disease even before lung CT changes. The normal range of hsCRP is 0.3–10 mg/L and about 86% of severe COVID patients had an average CRP above 39.4 mg/L. 10-fold rises in CRP levels have been observed in patients who died of COVID-19 than those who recovered from its severe form. CRP levels are raised in post-COVID depression. CRP may be a better marker in terms of cost-effectiveness for disease progression than procalcitonin (PCT), which is substantially expensive. CRP guides the prescription of antibiotics, as shown in [Figure 2]. However, the area circled in is grey and often confuses, but decision-making needs clinical acumen with other investigations such as X-ray and experience., Consumption of oral contraceptive pills, cardiovascular disorders, hypertension and sleep rhythm alteration with increase in the CRP level from its baseline and this needs attention; otherwise, CRP not affected by food intake.,
|Figure 2: CRP levels in prescription of antibiotics during viral infection. CRP: C-reactive protein|
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Interleukin-6 in corona virus diseases 2019
IL6 is produced in response to infection and injury to the tissues stimulates acute phase reactants synthesis in the liver, differentiation and proliferation of haematopoietic stem cells in bone marrow, antibody production and promotes T-cell cytotoxicity as host immune defence mechanism [Figure 3]., IL-6 is predominantly a proinflammatory cytokine and eliminates pathogens by enhancing innate immunity. Amongst COVID-19 patients, 50% were found to have an increased IL6 level and also associated with CS, which develops COVID complications such as respiratory failure requiring ventilatory support and death certainly. IL-6 signal transduction pathway is severe as a promising target to treat severe COVID-19 cases but is still under evaluation. Whereas monoclonal antibodies like tocilizumab and sarilumab were found to be effective in decreasing the disease severity. Plasma levels of IL6 are affected by temperature and thus requires centrifugation followed by storage at <4°C within 2 h of sample collection. EDTA was observed to be a better anticoagulant to estimate IL-6 levels. Estimation of plasma/serum IL6 levels in the sample obtained during evening and night is higher, which needs attention for diurnal variations. From our past experience, we do suggests recheck the values or repeat the IL6 estimation after 3 days if there is no clinical correlation.
|Figure 3: Infection and increase in IL6 and CRP which modulates phagocytosis in clearing microbes. IL: Interleukin, CRP: C-reactive protein|
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Procalcitonin in corona virus diseases 2019
PCT produced by parafollicular cells of the thyroid and is a potential marker in identifying systemic bacterial infections. PCT values falls after 24–35 h after treatment if there is a bacterial infection. In viral infection, the level of PCT remains below 0.01 g/L due to the inhibitory effect of IFN on PCT production. [Table 3] depicts guidelines for antibiotic therapy for septic shock using serum procalcitonin. However, in COVID infection, serial measurement of PCT predicts disease severity and prognosis. However, earlier study documents a few limitations like low sensitivity, high-cost per-test and repeated measurement., Although it is used to identify secondary bacterial infections during COVID infection, whether to initiate antibiotic therapy remain unanswered. Hence, we suggest PCT need to be combined with other parameters like CRP along with clinical correlation.
PCT value is falsely elevated in kidney diseases of various grades, hook effect is seen in very high PCT values, may estimate falsely low value, hetrophile antigen also needs to be considered.,
Ferritin and coronavirus diseases 2019
Serum ferritin levels reflect stored iron, and it is elevated in patients with iron overload diseases and decreased in iron deficiency anaemia. Nowadays, ferritin levels are used as an inflammatory marker in several chronic diseases, grouped as anaemia of chronic diseases and in hepatitis B virus infection and fibrosis. The raised ferritin during inflammation due to iron sequestration in the cells and making it unavailable for haematopoiesis, causing anaemia in chronic inflammation.,, Serum ferritin is regarded as a marker of immune dysregulation and immunosuppression and the activation of proinflammatory cytokines, which may contribute to CS. It is used to categorise the severity of COVID. Ferritin varies across laboratories, but levels of 30–300 ng/ml (male) and 10–200 ng/ml (female) are considered normal, but if <12 ng/ml indicates depletion of iron stores. In severe COVID, ferritin levels are 400–500 ng/mL when compared to normal subjects. A study showed the use of ferritin to PCT ratio likelihood of COVID-19 pneumonia. Still, how ferritin levels change during COVID-19 in chronic diseases has not been studied; thus, a cut-off to predict complications is required. Haemolysed samples must reject as it leads to false positive results and interpretation necessitates clinical correlation. Studies suggest replication of test sample due to biological variation, especially in females.,
| Cardiac Markers|| |
Cardiac involvement in COVID-19 infection can be of pre-existing cardiac comorbidities, hyperinflammatory phase/CS or adverse effects of drugs used during the treatment of COVID-19. SARS-CoV2 can directly infect the heart and cause myocarditis, destabilisation of pre-existing plaque. Moreover, arrhythmia was noted in a few patients due to hypoxia and electrolyte imbalance. Treatment regimen, including chloroquine, can affect the heart. Early injury in the myocardium can be detected by elevated cardiac enzymes, non-enzymatic markers include fatty acid-binding protein, myoglobin, ischaemia-modified albumin and cardiac troponin, electrocardiogram changes and other enzyme markers. Serial measurement of cardiac troponin can be valuable to start treatment for myocardial injury. Study documents that higher troponin (CTn) and CK levels are seen amongst critically ill patients and non-survivors compared to patients who were not critically ill or survived. A study from Wuhan, China, reported higher creatinine kinase-myocardial band, CK, lactate dehydrogenase (LDH), myoglobin and Cardiac troponin (TnI) amongst non-survivors when compared with survivors., Biomarkers pro adrenomedullin (pro-ADM), pro-endothelin-1 and proBNP are also significantly increased in patients with cardiac events in COVID-19 infection. According to the study, EDTA and heparin samples are known to interact with cTnI estimation which may give markedly lower value than serum in some cases, which requires attention. Other non-cardiac causes such as congestive cardiac failure, valvular diseases, hypertension, tachycardia, renal failure, drug ace inhibitors and hypothyroidism.
It is a marker of tissue injury specific to the cell membrane. Cardiac isoenzyme is elevated in myocardial injury, causing flipping of LDH. Hypoxia and lactate produced in muscle can cause myalgia, which can explain persistent myalgia in COVID-19 patients during infection. Hendry et al. had shown elevated LDH levels linked with a ~6-fold increase in odds of developing severe disease and a ~16-fold increase in odds of mortality in patients with COVID-19. The study suggests that patients must be managed in ICU if there is elevated LDH along with CRP patients may require a regular check-ups and prompt management.
LDH estimation affected by haemolysed blood samples can be rectification by training the phlebotomist and laboratory technologist. Also, it is increased in undiagnosed cancer patients, myocardial infarction, thyroid disease and tuberculosis which needs attention during interpretation.
Hepatic and renal markers
Liver enzymes are elevated in COVID-19-induced liver injury. These elevated transaminases may be due to pre-existing alcoholic liver hepatitis/cirrhosis or drug-induced hepatitis like antivirals, e.g., lopinavir, ritonavir and remdesivir which may warrant monitor of serum alanine aminotransferase (ALT) level along with bilirubin's and total protein and albumin. These markers were elevated even during multiorgan failure. Serum albumin as negative acute phase reactant levels decreases in inflammation and malnutrition.
Early study shows pre-COVID-19 observed a 30-fold increase in ACE2 expression in the liver of patients with hepatitis C virus-related cirrhosis in comparison with healthy individuals. Approximately 15%–65% of SARS-CoV2-infected individuals had abnormal liver function test with elevated serum ALT and aspartate aminotransferase levels in 29%–39% and 38%–63% of patients, respectively. Hypoalbuminaemia, a non-specific marker of illness severity, has been reported to be associated with worse COVID-19 outcomes, but severe liver injury, elevation in serum bilirubin level and synthetic liver dysfunction are all rare in patients infected with SARS-CoV2. Patients with cirrhosis have a high risk of respiratory failure following severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. This risk might occur through multiple converging pathways, including contributions from cirrhosis-associated immune dysfunction, acute hepatic decompensation and systemic inflammatory response. Cirrhosis-associated immune dysfunction could also lead to defective immune responses following SARS-CoV2 vaccination. Literature suggests that most patients with COVID-19 had abnormal renal function reflecting tubular, glomerular injury with decreased glomerular filtration rate, proteinuria, haematuria and few patients developed acute kidney injury with reduced survival rate., Death is even more in pre-existing kidney diseases with raised blood urea nitrogen, creatinine, and measuring these parameters helps to manage hypovolaemic shock along with electrolyte and arterial blood gas analysis and remains an ominous marker, especially after 3 weeks of the onset of symptoms. Mechanism of injury could be due to continuous viral shedding and immune complex deposition leading to thrombosis in vessels and decreased renal blood flow. In addition, hospital-acquired infection and drug toxicity can remain the cause for renal impairment identified by specific markers like BNP in right heart failure, troponin, D-dimers PCT, etc.,,
Haematological markers play a triage role in predicting the course and outcome of the SARS-CoV-2 infection and helpful in risk stratification and effective management. A simple, inexpensive and frequently performed test in COVID infection without much abnormality in RBC indices, whereas WBC counts rise only after severe infection. However, a study by Usal in the following parameters, et al. found a statistically significant difference between COVID-19 and non-COVID-19 patients. Similarly, a Meta-analysis of COVID-19 by Henry et al. compared various haematological parameters in fatal or severe and non-severe diseases.
The following count abnormalities are seen in severe COVID-19 patients:
Increased total leucocyte count and differential neutrophil count were more commonly seen in patients having severe COVID-19. The neutrophil–lymphocyte ratio and Neutrophil-Monocyte ratio are also elevated in patients with severe disease. Lymphopenia is the most common count abnormality reported in COVID-19, which occurs in up to 83% of COVID-19 patients. In severe patients, the count was even low, including low absolute lymphocyte count. In patients with severe disease, a reduction in both CD4 and CD8 lymphocytes was observed. It has been hypothesised that these lymphocytes play a crucial role in eliminating SARS virus-infected cells; maintaining a good number of circulating lymphocytes is essential for the recovery of COVID-19 patients. Hence, it is implicated that lymphocyte count, especially CD4 count, serves as a good indicator in predicting the outcome of COVID-19 patients. Regulatory T-cells are also found to be low in severe patients. Most COVID-19 patients have mild thrombocytopenia ranging from 100 to 150 × 109/L, and severe thrombocytopenia is rare. Cause for lymphocytopenia: the proposed cause for lymphocytopenia is apoptosis of lymphocytes mediated by excess cytokines, atrophy of lymphoid organs and lactic acidosis as in patients of cancer cachexia affects the proliferation of lymphocytes.,
Peripheral blood smear and bone marrow findings
- Increased reactive and plasmacytoid lymphocytes
- Significant left shift
- Occasional vacuolated neutrophils
- Leucoerythroblastic picture
- Fragmented RBCs
- Haemophagocytes in the bone marrow.
| Coagulation Parameters|| |
COVID-19 infection predisposes to hypercoagulable state, and it is associated with several thrombotic events (i.e. pulmonary embolism). The following coagulation parameters are associated with predicting the outcome of COVID-19 patients: D-dimer, prothrombin time (PT), activated partial thromboplastin time (APTT), lupus anticoagulant and Vwf.
| D-Dimer|| |
D-dimer is a fibrin degradation product released when a blood clot begins to break down and is used as a biomarker for thrombotic disorders. D-dimer value <0.5 μg/mL is usually considered normal, and values increase with increasing age and pregnancy. However, elevated D-dimers are seen in pulmonary embolism, deep vein thrombosis, disseminated intravascular coagulation (DIC), etc., Other coagulation markers associated with poor outcomes in COVID-19 patients are prolonged PT and APTT, elevated lupus anticoagulant and vWF levels. These findings strongly support the existence of a syndrome in COVID-19-associated coagulopathy characterised by derangements in clotting tests (PT and APTT), elevated D-dimer and an increased thrombotic tendency. International Society on thrombosis and haemostasis criteria for DIC can also be used to predict the likelihood of developing COVID-19-associated coagulopathy. A recent review by Bronic et al. has shown the possible laboratory error and recommendation for coagulation profile. Prompt rejection of improper samples is important for safe and valid reports.,
| Promising New Markers|| |
YKL-40, a glycoprotein from the family chitinase-3-like-1 protein is involved in the inflammatory changes of bronchioles and remodelling in pulmonary disorders. YKL-40 has pro-mitogenic action on lung fibroblast, which is associated with the severity of COVID-19 infection. A study by Michael et al. showed four promising markers such as sST2, sTNFRSF1A, IL-10 and IL-15, which are considered warning markers in blood as their circulatory levels are higher from hospital admission to till death. Amongst different blood groups, type 'O' is comparatively protective against SARS-CoV2. Studies on genetic polymorphism show that the severity of COVID-19 infection is linked to genes such as ACE2 gene, amino acid transporter (SLC6A20) and toll-like receptor (TLR7). Alamandine formed by the action of ACE 2 on Angiotension A through decarboxylation on angiotension (1–7) Alamandine has effect like vasodilatation and antifibrosis similar to angiotension (1–7) are markers.
| Conclusion|| |
Prediction of mortality by proper laboratory investigation is needed for better management of COVID-19-like infection in future with the diagnosis of SARS-CoV2 infection. Based on clinical features, prompt laboratory investigation is required, may the cause or consequence of the infection. Interpretation of the laboratory reports should also consider other variables and if needed, laboratories should promptly reject the samples or intimate clinician as in haemolysed and lipaemic samples, which may lead to wrong laboratory report and treatment.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]