PMC:7200337 / 57298-66713 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7200337","sourcedb":"PMC","sourceid":"7200337","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7200337","text":"Routine Bloodwork Biomarkers\nSeveral routine blood and serological parameters have been suggested to stratify patients who might be at higher risk for complications to aid in allocation of healthcare resources in the pandemic (Table 1 ). Serologic markers from routine bloodwork were reported by comparing patients with mild or moderate symptoms to those with severe symptoms. This includes different acute phase proteins, such as SAA (serum amyloid protein) and C-reactive protein (CRP) (Ji et al., 2020). Interestingly, elevations in CRP appear to be unique to COVID-19 patients when compared to other viral infections. Other consistently reported markers in non-survivors are increased procalcitonin (PCT) and IL-6 levels (Huang et al., 2020d), as well as increased serum urea, creatinine, cystatin C, direct bilirubin, and cholinesterase (Xiang et al., 2020a). Overall, inflammatory markers are common in severe cases of COVID-19 and appear to correlate with the severity of the symptoms and clinical outcome. Moreover, the extensive damage that occurs in specific organs of severe COVID-19 patients is possibly related to differences in the expression of ACE2 (Figure 5 ) (Du et al., 2020).\nTable 1 Routine Blood and Immunological Prognostic Biomarkers in COVID-19 Patients\nBiomarker Purpose\nRoutine Bloodwork Lymphocyte count Predicted the disease severity and the outcomes of hospitalized patients (Tan et al., 2020a).Prognostic value was confirmed in numerous studies (Huang et al., 2020d, Liu et al., 2020b, Song et al., 2020, Wang et al., 2020f, Wynants et al., 2020, Yan et al., 2020b, Yang et al., 2020b, Zhang et al., 2020c, Zhao et al., 2020d).Decreased continuously in non-surviving patients (Wang et al., 2020b).\nN/L Patients with N/L ≥3.13 were reported to be more likely to develop severe illness and to require ICU admission (Liu et al., 2020c).N/L on admission was a risk factor for short-term progression of patients with moderate pneumonia to severe pneumonia (Feng et al., 2020). Confirmed to be of prognostic value in COVID-19 in several studies (Song et al., 2020, Wynants et al., 2020, Zhou et al., 2020d).\nCRP Proposed as an early biomarker of disease progression (Ji et al., 2020). Even in early stages, CRP levels were positively correlated with lung lesions and reflected disease severity (Wang, 2020). Confirmed in numerous studies (Fu et al., 2020, Huang et al., 2020d, Wynants et al., 2020, Yan et al., 2020b, Zhao et al., 2020d, Zhou et al., 2020b). Predicted the risk of acute myocardial injury (Liu et al., 2020g, Xu et al., 2020a).\nLDH Higher in severe cases than in mild cases (Xiang et al., 2020a). Widely proposed to have prognostic value in COVID-19 (Huang et al., 2020d, Wynants et al., 2020, Yan et al., 2020b, Zhao et al., 2020d).\nD-dimer (and coagulation parameters) Predicted severity independently of other variables (Zhou et al., 2020d). Elevated levels and disseminated intravascular coagulation are found in non-survivors (Wang et al., 2020b). Identified patients at risk for acute cardiac injury (Liu et al., 2020g). Other coagulation parameters, such as fibrin degradation product levels, longer prothrombin time, and activated partial thromboplastin time, were also associated with poor prognosis (Tang et al., 2020a).\nSAA SAA was proposed to be used as an auxiliary index for diagnosis as it was elevated in 80% of the patients in a small cohort (Ji et al., 2020).\nNT-proBNP (N-terminal pro B type natriuretic peptide) NT-proBNP was an independent risk factor of in-hospital death in patients with severe COVID-19 (Gao et al., 2020b).\nPlatelet count High platelet-to-lymphocyte ratio was associated with worse outcome (Qu et al., 2020). Thrombocytopenia was associated with poor outcome and with incidence of myocardial injury in COVID-19 (Liu et al., 2020h, Shi et al., 2020).\nImmunological CD4+, CD8+, and NK cell counts Lower CD4+, CD8+, and NK cells in PBMCs correlated with severity of COVID-19 (Nie et al., 2020b). Validated by several studies (Wang et al., 2020f, Zheng et al., 2020b).\nPD-1 and Tim-3 expression on T cells Increasing PD-1 and Tim-3 expression on T cells could be detected as patients progressed from prodromal to overtly symptomatic stages (Diao et al., 2020). Expression was higher in infected patients versus healthy controls and in ICU versus non-ICU patients in both CD4 and CD8 T cells (Zhou et al., 2020b).\nphenotypic changes in peripheral blood monocytes The presence of a distinct population of monocytes with high forward scatter (CD11b+, CD14+, CD16+, CD68+, CD80+, CD163+, and CD206+, which secrete IL-6, IL-10, and TNF-α) was identified in patients requiring prolonged hospitalization and ICU admission (Zhang et al., 2020c). CD14+CD16+IL-6+ monocytes are increased in ICU patients (Zhou et al., 2020b).\nIP-10, MCP-3, and IL-1ra IP-10, MCP-3, and IL-1ra were, among 48 examined cytokines, the only ones that closely associated with disease severity and outcome of COVID-19 in a study by Yang et al. (Yang et al., 2020b).\nIL-6 Associated with disease severity (hospitalization and ICU admission) and poor prognosis (Chen et al., 2020g, Huang et al., 2020b, Liu et al., 2020b, Liu et al., 2020f, Wang et al., 2020b). Increased levels were associated with higher risk of respiratory failure (Yao et al., 2020b).\nIL-8 Positively correlated with disease severity (Chen et al., 2020e, Gong et al., 2020), with severe cases showing the highest IL-8 levels.\nIL-10 Increased in severe or critical patients as compared to mild patients (Gong et al., 2020, Zhou et al., 2020d) without a statistically significant difference between severe and critical cases (Gong et al., 2020).\nIL-2R Associated with disease severity in a study that, among other cytokines, also associated ferroprotein levels, PCT levels, and eosinophil counts with COVID-19 severity (Gong et al., 2020).\nIL-1β CD14+IL-1β+ monocytes are abundant in early-recovery patients as shown in a single-cell RNA-seq analysis and thought to be associated with cytokine storm (Wen et al., 2020). IL-1β did not correlate with disease severity in a cross-sectional study with mild, severe, and critical patients (Gong et al., 2020).\nIL-4 IL-4 was associated with impaired lung lesions (Fu et al., 2020), but some reports point to a potential mediator effect (Wen et al., 2020).\nIL-18 In modeling immune cell interaction between DCs and B cells in late recovery COVID-19 patients, IL-18 was found to be important in B cell production of antibodies, which suggests its importance in recovery (Wen et al., 2020).\nGM-CSF GM-CSF+IFN-γ+ T cells are higher in ICU than in non-ICU patients. CD14+CD16+GM-CSF+ monocytes are higher in COVID-19 patients as compared to healthy controls (Zhou et al., 2020b).\nIL-2 and IFN-γ IL-2 and IFN-γ levels were shown to be increased in severe cases (Liu et al., 2020b).\nanti-SARS-CoV-2 antibody levels Prolonged SARS-CoV-2 IgM positivity could be utilized as a predictive factor for poor recovery (Fu et al., 2020). Higher anti-SARS-CoV-2 IgG levels and higher N/L were more commonly found in severe cases (Zhang et al., 2020a).\nFigure 5 ACE2 Expression in Organs and Systems Most Frequently Implicated in COVID-19 Complications\nThe gastrointestinal tract, kidneys, and testis have the highest ACE2 expressions. In some organs, different cell types have remarkably distinct expressions; e.g., in the lungs, alveolar epithelial cells have higher ACE2 expression levels than bronchial epithelial cells; in the liver, ACE2 is not expressed in hepatocytes, Kupffer cells, or endothelial cells but is detected in cholangiocytes, which can explain liver injury to some extent. Furthermore, ACE2 expression is enriched on enterocytes of the small intestine compared to the colon.\nACE2, angiotensin-converting enzyme 2; BNP, B-type natriuretic peptide; CRP, C-reactive protein; IL, interleukin; N/L, neutrophil-to-lymphocyte ratio; PT, prothrombin time; aPTT, activated partial thromboplastin time.\nLymphopenia is the most frequently described prognostic marker in COVID-19 (Table 1), and it appears to predict morbidity and mortality even at early stages (Fei et al., 2020). Tan et al. proposed a prognostic model based on lymphocyte counts at two time points: patients with less than 20% lymphocytes at days 10–12 from the onset of symptoms and less than 5% at days 17–19 had the worst outcomes in this study (Tan et al., 2020a). Wynants et al. compared predictors of disease severity across seven studies (\u003e1,330 patients), highlighting CRP, neutrophil-to-lymphocyte ratio (N/L), and lactate dehydrogenase (LDH) as the most significant predictive biomarkers (Wynants et al., 2020). Furthermore, a meta-analysis of 30 COVID-19 studies with a total of 53,000 patients also attempted to identify early-stage patients with poor prognosis (Zhao et al., 2020d). The most consistent findings across the different studies were elevated levels of CRP, LDH, and D-dimer, as well as decreased blood platelet and lymphocyte counts (Yan et al., 2020b, Zhou et al., 2020d). Systemic and pulmonary thrombi have been reported with activation of the extrinsic coagulation cascade, involving dysfunctional endothelium and monocytic infiltration (Poor et al., 2020, Varga et al., 2020); thrombocytopenia and elevated D-dimer levels may be indicative of these coagulopathies in COVID-19 patients with important therapeutic implications (Fogarty et al., 2020, Poor et al., 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