Almost 5.7 million cases of COVID-19 have been confirmed worldwide, resulting in 355.653 deaths. For such a high volume of patients presenting at hospitals and other health care centers, accurate diagnosis and efficient markers for disease severity, therapeutic response, and disease outcome are key. Laboratory test biomarkers can play a useful role here.
The current standard for diagnosis of infection with SARS-CoV-2 is rRT-PCR. Blood gas analysis is valuable in diagnosis and predicting clinical worsening in COVID-19 patients, including in a patient subset that does not exhibit any obvious respiratory difficulties (‘happy hypozia’). In addition, identification of new laboratory tests capable of discriminating between severe and non-severe cases or patients at high or low risk of mortality will allow better risk stratification and appropriate allocation of resources [1, 2]. Mortality among patients with severe COVID-19 could be significantly reduced by early identification and timely treatment of critical cases . In some countries, biomarkers such as CRP, PCT, lymphopenia, and IL-6 and IL-10 are already being used to aid diagnosis or to provide early evidence of more severe disease progression .
Essential laboratory parameters
Routine laboratory examinations reveal a number of abnormalities in COVID-19 patients. A meta-analysis of 19 observational studies involving almost 3,000 patients with confirmed COVID-19 found that the most common laboratory features reported were decreased serum albumin (76% prevalence), elevated CRP (58%), elevated LDH (57%), lymphopenia (43%), and high ESR (42%) . Another review of eight smaller studies reported similar abnormalities in COVID-19 patients, i.e. lymphopenia (35-75%), elevated CRP (75-93%), LDH (27-92%), and ESR (up to 85% of cases) and low concentrations of serum albumin (50-98%), as well as increased D-dimer (36-43%) and low hemoglobin (41-50%) . Other abnormalities reported were increases in neutropenia, total bilirubin, creatinine, cardiac troponin, PT, and PCT .
Disease severity and risk stratification
Lymphopenia, neutrophilia, elevated serum ALT and AST levels, elevated LDH, CRP, and ferritin levels have been associated with greater disease severity [8, 9] and hospitalization  in COVID-19 patients. Patients with severe and fatal disease have significantly increased white blood cell (WBC) count, and decreased lymphocyte and platelet counts compared to those with non-severe disease and survivors [11,12]. CRP levels are markedly elevated in all patients, but significantly higher in severe than in non-severe cases. The elevated white blood cell and CRP levels in severe COVID-19 patients may reflect accompanying bacterial infection.
Elevated ALT, AST, and creatinine seen in severe cases suggests that COVID-19 carries an increased risk of impaired liver and kidney function. Biomarkers of inflammation such as IL-6 and IL-10, of cardiac injury, of liver and kidney function, and of coagulation measures are also significantly elevated in patients with both severe and fatal COVID-19. A recent meta-analysis of data from 21 studies concluded that WBC count, lymphocyte count, platelet count, IL-6, and serum ferritin should be closely monitor as markers for potential progression to critical illness .
A retrospective comparison of the hematological parameters between mild and severe cases showed that IL-6 and D-dimer were closely related to the occurrence of severe COVID-19 in adults, and their combined detection had the highest specificity and sensitivity for early prediction of the severity of COVID-19 . A similar result was reported from a pooled analysis of nine studies involving 1,779 COVID-19 patients, in which low platelet count was associated with increased risk of severe disease and mortality in patients and served as a clinical indicator of worsening illness during hospitalization, the researchers said .
Elevated D-dimer and lymphopenia have been associated with mortality in several studies [14,15]. Among a cohort of 799 COVID-19 patients, concentrations of ALT, AST, creatinine, CK, LDH, cardiac troponin I, N-terminal pro-brain natriuretic peptide, and D-dimer were markedly higher in patients who died compared with those who recovered .
Correlation between abnormal coagulation parameters and disease severity
Abnormal coagulation parameters are associated with poor prognosis in COVID-19 patients. D-dimer is commonly elevated in patients with COVID-19, especially in older individuals and those with comorbidities who are at higher risk of dying from COVID-19. D-dimer level correlates with disease severity [17, 18] and is a reliable prognostic marker for in-hospital mortality [17,19]. Higher D-dimer levels on admission are linked to patients needing critical care support .
In a large analysis of data from 1,099 patients with laboratory-confirmed COVID-19 from over 550 hospitals in China, raised D-dimer (≥0.5 mg/L) was recorded in 46% of patients, 43% with non-severe, but 60% with severe illness . PT was slightly prolonged in non-survivors at admission versus survivors and in those who needed critical care support versus the non-ICU cohort.
The International Society of Thrombosis and Haemostasis (ISTH) recommends measurement of D-dimers, prothrombin time and platelet count in all patients with COVID-19 infection . Patients who have markedly raised D-dimers (3-4 fold increase), should be admitted to hospital even in the absence of other severity symptoms. In addition, the ISTH suggests that serum fibrinogen measurement may be valuable for diagnosis of DIC .
Measuring inflammatory markers
Patients with critical illness have high plasma levels of inflammatory markers, suggesting potential immune dysregulation. [22, 24] Higher serum levels of pro-inflammatory cytokines (TNFα, IL-1, and IL-6) and chemokines (IL-8) were found in patients with severe COVID-19 compared with individuals with mild disease, similar to results seen in SARS and MERS and suggest a role for hyperinflammatory responses in COVID-19 pathogenesis . This excessive immune response, called a cytokine storm, arises from overproduction of early response proinflammatory cytokines such as TNF, IL-6, and IL-1β and can lead to ARDS, multi-organ failure, and, ultimately, death.
UK researchers recommend that all patients with severe COVID-19 should be screened for hyperinflammation using laboratory trends (e.g. increasing ferritin, decreasing platelet counts, or erythrocyte sedimentation rate) to identify patients that can be treated with immunosuppressive therapies such as steroids, intravenous immunoglobulin, selective cytokine blockade or JAK inhibition . Based on a study of 4,000 patients hospitalized in New York City, in whom D-dimer, ferritin, and CRP were strongly associated with critical illness, NYU Grossman School of Medicine researchers recommend routine measurement of inflammatory markers during COVID-19 hospitalization .
PCT is typically normal on admission, as in other viral infections, but it may increase in COVID-19 patients admitted to ICU [3, 20, 26]. In a pooled analysis of four studies, increased PCT was associated with an almost five-fold higher risk of severe SARS-CoV-2 infection . This may represent a bacterial coinfection in these patients, but it could also be a marker of severity of ARDS or the result of immune dysregulation that increases the production of cytokines that increase procalcitonin synthesis .
CK and LDH
COVID-19 mRNA clearance ratio has been identified as significantly correlated with a fall in serum CK and LDH levels that could predict a favorable outcome in COVID-19 infected patients . In recently published studies, myalgia or fatigue affected 44-70% of hospitalized patients and increased CK was present in up to 33% of admitted patients . Other coronavirus infections are associated with myalgias and elevated CK and rhabdomyolysis, suggesting that coronavirus infections may cause viral myositis.
Cardiac and kidney injury markers
COVID-19 infections are associated with increased levels of cardiac biomarkers due to myocardial injury probably associated with infection-induced myocarditis and ischemia . In multivariable adjusted models, cardiac injury is significantly and independently associated with mortality. Similarly, elevated troponin levels due to cardiac injury are associated with significantly higher mortality . Severe COVID-19 infections are also potentially associated with cardiac arrhythmias at least in part due to infection-related myocarditis.
It is not yet known whether the kidneys are a major target of the virus. [33, 34]. Renal impairment has been reported to be common in COVID-19 patients , and AKI frequently develops during hospitalization for COVID-19 and is associated with in-hospital mortality. Monitoring kidney function in COVID-19 is recommended especially in patients with elevated plasma creatinine . A small study of 59 patients infected with SARS-CoV-2 reported  that 63% of patients exhibited proteinuria, and 19% and 27% respectively had elevated plasma creatinine and blood urea nitrogen. Based on these findings it was concluded that laboratory criteria such as levels of IL-6 and other cytokines as well as cell cycle arrest biomarkers with high predictive value for AKI could represent objective and standardized criteria to guide therapy.
More data needed
No biomarker or combination of biomarkers currently exists that is sensitive or specific enough to establish a diagnosis of COVID-19, or to pragmatically predict its clinical course. To date, most of the relevant data on COVID-19 has come from case series or observational studies. As more data become available and more prospective studies are reported, laboratory parameters may emerge that can discriminate between severe and non-severe cases, or patients at high or low risk of mortality.
List of Abbreviations
AKI: acute kidney injury
ALT: alanine aminotransferase
ARDS: acute respiratory distress syndrome
AST: aspartate aminotransferase
CEBM: Centre for Evidence-Based Medicine (UK)
CK: creatine kinase
COVID-19: novel coronavirus disease 2019
CRP: C-reactive protein
DIC: disseminated intravascular coagulation
ESR: erythrocyte sedimentation rate
ICU: intensive care unit
IL-6: interleukin 6
IL-8: interleukin 8
IL-10: interleukin 10
LDH: lactate dehydrogenase
MERS: Middle Eastern respiratory syndrome
PT: prothrombin time
rRT-PCR: real-time reverse transcription polymerase chain reaction
SARS: severe acute respiratory syndrome
SARS-CoV-2: severe acute respiratory syndrome coronavirus 2
TNFα: tumor necrosis factor α
Henry BM, Santos de Oliveira MH, Benoit S, et al. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis. Clin Chem Lab Med. Published online April 10, 2020. DOI: 10.1515/cclm-2020-0369;
Xie J, Hungerford D, Chen H, et al. Development and external validation of a prognostic multivariable model on admission for hospitalized patients with COVID-19. medRxiv. Preprint published online April 7, 2020. DOI: 10.1101/2020.03.28.20045997;
Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study, Lancet. 2020;395:507–13. DOI: 10.1016/S0140-6736(20)30211-7;
Green K, Allen AJ, Sukla J, et al. What is the role of imaging and biomarkers within the current testing strategy for the diagnosis of Covid-19? The Centre for Evidence-Based Medicine at the University of Oxford. April 8, 2020. https://www.cebm.net/covid-19/what-is-the-role-of-imaging-and-biomarkers-within-the-current-testing-strategy-for-the-diagnosis-of-covid-19/;
Rodriguez-Morales AJ, Cardona-Ospinaa JA, Gutiérrez-Ocampoa E, et al; Latin American Network of Coronavirus Disease 2019-COVID-19 Research (LANCOVID-19). Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis. Travel Med Infect Dis. Published online March 13, 2020. DOI: 10.1016/j.tmaid.2020.101623;
Lippi G, Plebani M. Laboratory abnormalities in patients with COVID-2019 infection Clin Chem Lab Med. Published online March 3, 2020. DOI: 10.1515/cclm-2020-0198;
Lippi G, Plebani M. The critical role of laboratory medicine during coronavirus disease 2019 (COVID-19) and other viral outbreaks. Clin Chem Lab Med. 2020 Published online March 19, 2020. DOI: 10.1515/cclm-2020-0240;
Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID‑19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. Published online March 3, 2020. DOI: 10.1007/s00134-020-05991-x;
Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med.
Published online February 24, 2020.
Tan C, Huang Y, Shi F, et al. C-reactive protein correlates with CT findings and predicts severe COVID-19 early. J Med Virol. Published online April 13, 2020. DOI: 10.1002/jmv.25871;
Henry B, Lippi G, Plebani M. Laboratory abnormalities in children with novel coronavirus disease 2019. Clin Chem Lab Med. Published online March 16, 2020. DOI:10.1515/cclm-2020-0272,
Cao W, Shi L, Chen L, et al. Clinical features and laboratory inspection of novel coronavirus pneumonia (COVID-19) in Xiangyang, Hubei. medRxiv. Preprint published online February 25, 2020. DOI: 10.1101/2020.02.23.20026963;
Lippi G, Plebani M. Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis. Clin Chim Acta. 2020;505:190–1. DOI: 10.1016/j.cca.2020.03.004;
Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. Published online March 13, 2020. DOI:10.1001/jamainternmed.2020.0994;
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. Published online March 9, 2020. DOI: 10.1016/S0140-6736(20)30566-3;
Petrilli CM, Jones SA, Yang J, et al. Factors associated with hospitalization and critical illness among 4,103 patients with Covid-19 disease in New York City. medRxiv. Preprint published online April 11, 2020. DOI: 10.1101/2020.04.08.20057794;
Yao Y, Cao J, Wang Q, et al. D-dimer as a biomarker for disease severity and mortality in COVID-19 patients: a case control study. Research Square. Preprint posted April 3, 2020. DOI: 10.21203/rs.3.rs-20850/v1;
Lippi G, Favaloro E. D-dimer is associated with severity of coronavirus disease 2019: a pooled analysis Thromb Haemost. Published online April 3, 2020.
Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18:844-7. DOI: 10.1111/jth.14768;
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506. https://doi.org/10.1016/S0140-6736(20)30183-5;
Guan WJ, Ni ZY, Hu Y, et al; China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. Published online February 28, 2020. DOI: 10.1056/NEJMoa2002032;
Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. Published online March 25, 2020. DOI: 10.1111/JTH.14810;
Wada H, Thachil J, Di Nisio M, et al; The Scientific Standardization Committee on DIC of the International Society on Thrombosis Haemostasis. Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines.. J Thromb Haemost. Published online April 11, 2013. DOI: 10.1111/jth.12155;
Qin C, Zhou L, Hu Z, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. Published online March 12, 2020.
Mehta P, McAuley DF, Brown M, et al. HLH Across Specialty Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. Published online March 12, 2020. DOI: 10.1016/S0140-6736(20)30630-9
Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA. 2020;323:1061–9. DOI:10.1001/jama.2020.1585;
Lippi G, Plebani M, Henry BM. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clin Chim Acta. 2020;506:145–8. DOI: 10.1016/j.cca.2020.03.022;
Shah V. Meaning of elevated procalcitonin unclear in COVID-19. Massachusetts General Hospital: Advances in Motion. April 20, 2020. https://advances.massgeneral.org/research-and-innovation/article.aspx?id=1174;
Yuan J, Zou R, Zeng L, et al. The correlation between viral clearance and biochemical outcomes of 94 COVID‑19 infected discharged patients. Inflamm Res. Published online March 29, 2020. DOI: 10.1007/s00011-020-01342-0;
Guidon AC, Amato AA. COVID-19 and neuromuscular disorders. Neurology. Published online April 13, 2020. DOI: 10.1212/WNL.0000000000009566;
Madjid M, Safavi-Naeini P, Solomon SD, et al. Potential effects of coronaviruses on the cardiovascular system. A review. JAMA Cardiol. Published online March 27, 2020. doi:10.1001/jamacardio.2020.1286;
Guo T, Fan Y, Chen M, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol. Published online March 27, 2020. doi:10.1001/jamacardio.2020.1017;
Ronco C, Reis T. Kidney involvement in COVID-19 and rationale for extracorporeal therapies. Nat Rev Nephrol. Published online April 9, 2020. DOI: 10.1038/s41581-020-0284-7;
Wang L, Li X, Chen H, et al, Coronavirus disease 19 infection does not result in acute kidney injury: an analysis of 116 hospitalized patients from Wuhan, China. Am J Nephrol. Published online March 31, 2020. DOI: 10.1159/000507471;
Cheng Y, Luo1 R, Wang K, et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int. Kidney Int. Published online March 20, 2020. DOI: 10.1016/j.kint.2020.03.005;
Xiao G, Hu H, Wu F, et al. Acute kidney injury in patients hospitalized with COVID-19 in Wuhan, China: A single-center retrospective observational study. medRxiv. Preprint published online April 6, 2020. DOI: DOI: 10.1101/2020.04.06.20055194;
Li Z, Wu M, Guo J, Yao J, et al; Anti-2019-nCov Volunteers. Caution on kidney dysfunctions of 2019-ncov patients. MedRvix. Published online March 27, 2020. doi: DOI: 10.1101/2020.02.08.20021212.
- All References last accessed April 24, 2020.
- The statements by Siemens Healthineers customers described herein are based on results that were achieved in the customer’s unique setting. Since there is no “typical” hospital and many variables exist (e.g., hospital size, case mix, level of IT adoption) there can be no guarantee that other customers will achieve the same results.