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 Table of Contents  
Year : 2021  |  Volume : 11  |  Issue : 2  |  Page : 42-47

Pathological and biochemical alteration in COVID-19

Senior Physician, Digboi Assam, India

Date of Submission23-Jul-2021
Date of Acceptance27-Jul-2021
Date of Web Publication05-Oct-2021

Correspondence Address:
Dr. Noni Gopal Singha
H. No. 399, Near Nepali Thakurbari, PO – Digboi Dist-Tinsukia 786173, Assam
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajoim.ajoim_17_21

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Corona virus disease 2019 (COVID-19) caused by severe acute respiratory corona virus 2 (SARS-COV-2) is mainly respiratory disease occurring since December 2019 and first detected in Wuhan province of China. The complexity of SARSCOV-2 is centered on the unpredictable clinical course of the disease that can rapidly develop causing severe and deadly outcomes. The pandemic COVID-19 is a scientific, medical, and social challenge. In this review, the basic pathological and biochemical changes in COVID-19 are described, also how it influences in predicting the disease progression thereby helping in early interventions to prevent complications.

Keywords: Betacoronavirus, Covid-19, phylogenetic analysis

How to cite this article:
Singha NG. Pathological and biochemical alteration in COVID-19. Assam J Intern Med 2021;11:42-7

How to cite this URL:
Singha NG. Pathological and biochemical alteration in COVID-19. Assam J Intern Med [serial online] 2021 [cited 2022 Aug 14];11:42-7. Available from: http://www.ajimedicine.com/text.asp?2021/11/2/42/327543

  Introduction Top

Coronaviruses are a diverse group of viruses infecting many different animals, and they can cause mild-to-severe respiratory infections in humans. In 2002 and 2012, respectively, two highly pathogenic coronaviruses with zoonotic origin, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), emerged in humans and caused fatal respiratory illness. At the end of 2019, a novel corona virus designated as SARS-CoV-2 emerged in the city of Wuhan, China, and caused an outbreak of unusual viral pneumonia. Being highly transmissible, this novel coronavirus disease, also known as coronavirus disease 2019 (COVID-19), has spread fast all over the world.[1],[2] The ongoing outbreak of COVID-19 has posed an extraordinary threat to global public health. Although genetic evidence suggests that SARS-CoV-2 is a natural virus that likely originated in animals, there is no conclusion yet about when and where the virus first entered humans. As some of the first reported cases in Wuhan had no epidemiological link to the seafood market,[3] it has been suggested that the market may not be the initial source of human infection with SARS-CoV-2.

  Genomics, Phylogeny, and Taxonomy Top

As a novel betacoronavirus, SARS-CoV-2 shares 79% genome sequence identity with SARS-CoV and 50% with MERS-CoV24. Its genome organization is shared with other betacoronaviruses. The six functional open reading frames (ORFs) are arranged in order from 5′ to 3′: replicase (ORF1a/ORF1b), spike (S), envelope (E), membrane (M), and nucleocapsid (N). In addition, seven putative ORFs encoding accessory proteins are interspersed between the structural genes.[4] Most of the proteins encoded by SARS-CoV-2 have a similar length to the corresponding proteins in SARS-CoV. Of the four structural genes, SARS-CoV-2 shares more than 90% amino acid identity with SARS-CoV except for the S gene, which diverges.[5],[6] The replicase gene covers two-thirds of the 5′ genome and encodes a large polyprotein (pp1ab), which is proteolytically cleaved into 16 non-structural proteins that are involved in transcription and virus replication. Most of these SARS-CoV-2 non-structural proteins have greater than 85% amino acid sequence identity with SARS-CoV4.

The phylogenetic analysis for the whole genome shows that SARS-CoV-2 is clustered with SARS-CoV and SARS-related coronaviruses (SARSr-CoVs) found in bats, placing it in the subgenus Sarbecovirus of the genus Betacoronavirus. The SARS-CoV-2 S protein has a full size of 1273 amino acids, longer than that of SARS-CoV (1,255 amino acids) and known bat SARSr-CoVs (1245–1269 amino acids). It is distinct from the S proteins of most members in the subgenus Sarbecovirus, sharing amino acid sequence similarities of 76.7–77.0% with SARS-CoVs from civets and humans, 75–97.7% with bat coronaviruses in the same subgenus, and 90.7–92.6% with pangolin coronaviruses.[6] In the receptor-binding domain (RBD) of S protein, the amino acid similarity between SARS-CoV-2 and SARS-CoV is only 73%.

  Pathogenesis Top

SARS-CoV-2 uses the same receptor as SARS-CoV, angiotensin-converting enzyme 2 (ACE2).[6],[7] Besides human ACE2 (hACE2), SARS-CoV-2 also recognizes ACE2 from pig, ferret, rhesus monkey, civet, cat, pangolin, rabbit, and dog.[6],[8],[9],[10] The broad receptor usage of SARS-CoV-2 implies that it may have a wide host range, and the varied efficiency of ACE2 usage in different animals may indicate their different susceptibilities to SARS-CoV-2 infection. It is to be noted that the affinity of the S protein to ACE-2 is said to be exceedingly higher (at least 10–20 times) when compared with that of a similar protein on SARS-CoV-1, and the ACE-2 expression depends on the genetic factors, age, and sex. This explains a very low case fatality rate (CFR) in pediatric patients compared with patients beyond 80 years of age (CFR of 0% for individuals under 8 years of age vs. 21.9% for patients above 80 years). Unfortunately, the ACE-2 expression also increases in the presence of co-morbid conditions such as obesity, pre-existing chronic cardiopulmonary disease, cancer, and use of immunosuppressive drugs, and such patients are prone to develop severe disease.

The S1 subunit of a coronavirus is further divided into two functional domains: an N-terminal domain and a C-terminal domain. Structural and biochemical analyses identified a 211 amino acid region (amino acids 319–529) at the S1 C-terminal domain of SARS-CoV-2 as the RBD, which has a key role in virus entry and is the target of neutralizing antibodies.[11],[12] The RBM mediates contact with the ACE2 receptor (amino acids 437–507 of SARS-CoV-2 S protein), and this region in SARS-CoV-2 differs from that in SARS-CoV in the five residues critical for ACE2 binding, namely, Y455L, L486F, N493Q, D494S, and T501N5. Owing to these residue changes, interaction of SARS-CoV-2 with its receptor stabilizes the two virus-binding hotspots on the surface of hACE2.[11] Moreover, a four-residue motif in the RBM of SARS-CoV-2 (amino acids 482–485: G-V-E-G) results in a more compact conformation of its hACE2-binding ridge than in SARS-CoV and enables better contact with the N-terminal helix of hACE2.[11] Biochemical data confirmed that the structural features of the SARS-CoV-2 RBD have strengthened its hACE2 binding affinity compared with that of SARS-CoV.[11],[13],[14] It has been shown that host proteases participate in the cleavage of the S protein and activate the entry of SARS-CoV-2, including transmembrane protease serine protease 2 (TMPRSS2), cathepsin L, and furin.[7],[15],[16] Single-cell RNA sequencing data showed that TMPRSS2 is highly expressed in several tissues and body sites and is co-expressed with ACE2 in nasal epithelial cells, lungs, and bronchial branches, which explains some of the tissue tropism of SARS-CoV-2.[17],[18] SARS-CoV-2 pseudovirus entry assays revealed that TMPRSS2 and cathepsin L have cumulative effects with furin on activating virus entry.[16]

The pathogenesis of SARS-CoV-2 infection in humans manifests itself as mild symptoms to severe respiratory failure. On binding to epithelial cells in the respiratory tract, SARS-CoV-2 starts replicating and migrating down to the airways and enters alveolar epithelial cells in the lungs. The rapid replication of SARS-CoV-2 in the lungs may trigger a strong immune response. Cytokine storm syndrome causes acute respiratory distress syndrome and respiratory failure, which is considered the main cause of death in patients with COVID-19.[19],[20] Histopathological changes in patients with COVID-19 occur mainly in the lungs. Histopathology analyses showed bilateral diffused alveolar damage, hyaline membrane formation, desquamation of pneumocytes, and fibrin deposits in lungs of patients with severe COVID-19. Exudative inflammation was also shown in some cases. Immunohistochemistry assays detected SARS-CoV-2 antigen in the upper airway, bronchiolar epithelium, and submucosal gland epithelium, as well as in type I and type II pneumocytes, alveolar macrophages, and hyaline membranes in the lungs.[19],[21-23]

  Markers of COVID-19 Infection and Severe Progression Top

A pattern of hematologic, biochemical, inflammatory, and immune biomarker abnormalities has been identified in patients with severe disease compared with mild systemic disease and warrants inclusion in risk stratification models [Table 1].
Table 1: Biomarker abnormalities in COVID-19 patients with severe systemic disease

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  Hematologic Biomarkers Top

Hematologic biomarkers used to stratify COVID-19 patients include white blood cell (WBC) count, lymphocyte count, neutrophil count, neutrophil–lymphocyte ratio (NLR), platelet count, eosinophil count, and hemoglobin. Yang et al.[24] reported lymphopenia in 80% of critically ill adult COVID-19 patients, whereas Chen et al.[21] reported a rate of only 25% of patients with mild COVID-19 infection. These observations suggest that lymphopenia may correlate with infection severity. Qin et al.[25] analyzed markers related to dysregulation of immune response in a cohort of 450 COVID-19-positive patients, reporting that severe cases tended to have lower lymphocyte-, higher leukocyte-counts and higher NLR, as well as lower percentages of monocytes, eosinophils, and basophils compared with mild cases. Similarly, Henry et al.[26] also concluded in a meta-analysis on 21 studies including 3377 COVID-19-positive patients that those with severe and fatal disease had significantly increased WBC and decreased lymphocyte and platelet counts when compared with non-severe disease and survivors.

In a study of 32 COVID-19 patients, decreased eosinophil count was registered in 66%.[27] Eosinophil counts have been positively correlated to lymphocyte count. In another study of 140 COVID-19 patients, eosinopenia was reported in 52.9% and the eosinophil count was positively associated with lymphocyte count in mild and severe cases of COVID19.[28] Du et al.[29] reported very low eosinophil counts in 81.2% of the patients at admission, which may indicate poor prognosis. Liu et al.[30] also reported low eosinophil values on initial hospitalization, which reportedly returned to normal before discharge, concluding that increasing eosinophils may be an indicator of clinical COVID-19 improvement. However, results from a systematic literature review concluded that “eosinopenia may not be associated with unfavorable progression of COVID19.”[31] Therefore, the diagnostic value of eosinopenia in COVID-19 requires further investigation with larger patient cohorts to establish the sensitivity and specificity of the eosinophil count.

As platelet count is a simple, cheap, and easily available biomarker and has been independently associated with disease severity and mortality risk in intensive care unit, it has been rapidly adopted as a potential biomarker for COVID-19 patients. The number of platelets was reported to be significantly reduced in COVID-19 patients[32],[33] and was lower in non-survivor patients compared with survivors. Low platelet count has been associated with increased risk of severe disease and mortality for COVID-19 patients and can serve as an indicator of clinical disease worsening during hospitalization.[34] Another research group found that patients with severe pneumonia induced by SARS-CoV-2 had higher platelet count than those induced by non-SARS-CoV-2. The patients with significantly elevated platelets and higher platelet-to-lymphocyte ratio during treatment had longer average hospitalization days.[35] Damaged lung tissue and pulmonary endothelial cells may activate platelets in the lungs, resulting in the aggregation and formation of microthrombi, thereby increasing platelet consumption. In severe disease, WBCs show lymphocytopenia, affecting both CD4 and CD8 cells, as well as a decrease in monocytes and eosinophils, and a clear increase in neutrophils and NLR. These simple parameters can be used for early diagnosis and identification of critically ill patients.[26]

  Biochemical Biomarkers Top

The main laboratory changes in severe or fatal COVID-19 patients were recently explored in a meta-analysis, including three large studies comparing survivors with non-survivors. A significant increase in total bilirubin and creatine kinase (CK), together with serum ferritin, WBC count, and interleukin (IL)-6, was registered in non-survivors when compared with survivors.[36],[37] Further, given the strong association between thrombo-embolism and COVID-19 and to a lesser extent, myocardial injury, D-dimer and cardiac markers are crucial in COVID-19 patient monitoring.

Markers of muscular and in particular cardiac injury were elevated in patients with both severe and fatal COVID-19. Chen et al.[38] observed in a cohort of 799 patients (113 non-survivors and 161 recovered) markedly higher concentrations of alanine transaminase (ALT), aspartate transaminase (AST), creatinine, CK, lactate dehydrogenase (LDH), cardiac troponin I, N-terminal pro-brain natriuretic peptide, and D-dimer in non-survivors compared with recovered patients. Liver function has also been identified as an important predictor for COVID-19 patient mortality. A recent study suggested that SARS-CoV-2 may directly bind to ACE2-positive cholangiocytes, and therefore, liver abnormalities in COVID-19 patients may be due to cholangiocyte dysfunction and other causes such as drug-induced and systemic inflammatory response-induced liver injuries.[39] Regarding the specific and dynamic pattern of liver injury parameters, Lei et al.,[40] in a wide retrospective multicenter study involving a COVID-19 cohort-derived data set of 5771 patients, reported that AST is strongly associated with mortality risk compared with other parameters, reflecting liver injury. This evidence is in contrast to the evidence of ALT elevation in other hepatitis-induced liver injury.

  Inflammatory Biomarkers Top

The increase in inflammation markers is the critical point underlying the systemic vasculitic processes and the defects in the coagulation processes that cause most parenchymal lesions in vital organs. The C-reactive protein (CRP) marker was found to be significantly increased in the initial phases of the infection for severe COVID-19 patients, also prior to indications of critical findings with computed tomography. Importantly, CRP has been associated with disease development and is an early predictor for severe COVID-1.[40]

The immunological biomarkers of IL-6 and serum ferritin are reported to be significantly increased in non-survivors vs. survivors.[26] The significant increase of inflammatory cytokines, such as IL-6, is connected to a so-called “cytokine storm,” behind acute lung injury and acute respiratory distress syndrome and can lead to further tissue damage and multi-organ failure.[41] This hyperbolic systemic inflammation relates to lymphopenia and is associated with severe disease. Current clinical practice suggests that the determination of IL-6, D-dimer, LDH, and transaminases in addition to routine laboratory tests is useful for the stratification of high-risk patients and the identification of those who might potentially benefit from anti-IL-6 immunotherapies with tocilizumab.[42]

  Coagulation Biomarkers Top

Abnormal coagulation parameters are associated with poor prognosis. Specifically, markedly elevated D-dimer and fibrin degradation products (FDPs) are common in COVID-19 non-survivor patients.[43] D-dimer appears to be frequently increased in patients with COVID-19 (36–43%)[44] and may be related to severe complications and death. In some large-scale studies, PT has been shown to be correlated to disease severity. In a retrospective study involving 296 COVID-19 patients (with 17 non-survivors), the non-survivor group had higher D-dimer and thrombin time and lower activated partial thromboplastin time (aPTT) than the survivor group.[45] Tang et al.[43] investigated 207 non-survivor COVID-19 patients and revealed that non-survivors had remarkably higher D-dimer and FDP levels and longer PT at admission compared with survivors. Terpos et al.[46] showed that blood hypercoagulability is common among hospitalized COVID-19 patients. They reported that coagulation abnormalities in PT, aPTT, FDP, and D-dimer, along with severe thrombocytopenia, are associated with life-threatening disseminated intravascular coagulation, which necessitates continuous vigilance and prompt intervention. In large-scale studies, D-dimer and PT have been found to be associated with severe disease and death.[47]

  Conclusion Top

It is necessary to determine risk categories following COVID-19 diagnosis, to ensure an optimal resource allocation, and to improve clinical management and prevention of serious complications. To sum up, we can conclude from the analysis of published studies that hematological (lymphocyte count, neutrophil count, and NLR), inflammatory (CRP, erythrocyte sedimentation rate, IL-6), and especially biochemical (D dimer, troponins, CK) parameters correlate with severe prognosis or exitus in COVID-19 patients and can therefore be used as predictive biomarkers. Coagulation and liver parameters might play a crucial role in identifying severe cases of COVID-19.

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