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Laboratory characteristics of patients infected with the novel SARS-CoV-2 virus

  • Author Footnotes
    1 Both the authors contributed equally to this work.
    Chrysanthi Skevaki
    Footnotes
    1 Both the authors contributed equally to this work.
    Affiliations
    Institute of Laboratory Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Philipps Universität Marburg, German Center for Lung Research (DZL) Marburg, Baldinger Straße, 35043 Marburg, Germany
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  • Author Footnotes
    1 Both the authors contributed equally to this work.
    Paraskevi C. Fragkou
    Footnotes
    1 Both the authors contributed equally to this work.
    Affiliations
    4th Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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  • Chongsheng Cheng
    Affiliations
    Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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  • Min Xie
    Affiliations
    Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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  • Harald Renz
    Correspondence
    Corresponding address.
    Affiliations
    Institute of Laboratory Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Philipps Universität Marburg, German Center for Lung Research (DZL) Marburg, Baldinger Straße, 35043 Marburg, Germany
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  • Author Footnotes
    1 Both the authors contributed equally to this work.

      Summary

      A subgroup of COVID-19 patients develop very severe disease with requirement for ICU treatment, ventilation, and ECMO therapy. Laboratory tests indicate that the immune and clotting system show marked alterations with hyper-activation, hyper-inflammation, cytokine storm development. Furthermore, organ-specific biomarkers demonstrate the involvement of cardiac muscle, kidney, and liver dysfunction in many patients. In this article the use of laboratory biomarkers is discussed with regard to their use for diagnosis, disease progression, and risk assessment.

      Keywords

      Introduction

      Although only a minority of COVID-19 patients show critical disease progression from moderate to severe stages of the disease including requirement for ventilation and ECMO therapy, this subgroup of COVID-19 patients requires particular attention. Data collection from several regions of the world including China, Europe, and the United States clearly demonstrate that COVID-19 is not only a disease of the lung and the airways. Many other organ systems are involved and contribute to disease variety and progression. With regard to the immune system, hyper-inflammation together with the development of exorbitant increased cytokine production represents a hallmark of severe patients requiring ventilation. Some of these patients develop bacterial superinfections with increased levels of sepsis markers. Another important systems which recently caused increased attention is the clotting system. This is particularly highlighted by the detection of increased levels of D-dimers. Organ dysfunction has been reported in many patients including the heart (myocardial muscle damage), the kidney, and the liver. Laboratory diagnostics play not only an important role in disease diagnosis, but also in assessing progression and severity in these patients. Furthermore, laboratory diagnostics allow early detection of organ dysfunction in many cases. Moreover, biotests are used to assess an increased mortality risk in severe lethal patients. In this article we summarize the most prominent findings in COVID-19 patients and discuss the use of these markers for diagnosis, disease progression, and risk assessment. (Fig. 1 and Table 1, Table 2)
      Fig. 1
      Fig. 1Schematic overview of key laboratory characteristics during SARS-CoV-2 infections. The latter induce an increase (depicted in red) or a reduction (depicted in green) in the concentration and/or counts of a wide range of laboratory biomarkers. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
      Table 1Laboratory parameters and associated pathophysiology in adult COVID-19 patients.
      BIOMARKERPATHOPHYSIOLOGYCLINICAL UTILITY IN ADULT COVID-19REFERENCES
      Hematological indices
      HemoglobinReduced erythropoiesis due to inflammatory cytokinesLower levels associated with: Lack of improvement

      No clear association with disease severity and outcomes
      (16, 5, 11)
      LymphocytesAbsolute count reduction, functional exhaustion of all populations (especially cytotoxic T-cells) Unknown exact mechanismsLower levels associated with: ↑Severity, ↑Mortality

      PMN/CD8+ ratio and PMN/Lymphocyte ratio may be used as prognostic markers
      (52, 5, 1–4, 6, 10–13, 7)
      Monocytes/

      Basophils/

      Eosinophils
      Absolute count reduction,

      Unknown exact mechanisms
      No clear association with disease severity and outcomes(14, 3, 10)
      Total white blood cells/NeutrophilsIncreased due to inflammationHigher levels associated with: ↑Severity, ↑Mortality, Bacterial superinfections(1–4)
      Acute phase reactants
      AlbuminReduced production due to inflammatory cytokinesLower levels associated with: ↑Severity, ↑Mortality, Lack of improvement

      Low levels on admission may be used as prognostic marker for severity
      (1, 2, 11, 6, 16, 19)
      C-reactive protein (CRP)Increased production due to inflammatory cytokinesHigher levels associated with: ↑Severity, Lack of improvement, Bacterial superinfections(1, 3, 16)
      Erythrocyte sedimentation rateIncreased in inflammationTendency for higher levels associated with: ↑Mortality(1)
      FerritinIncreased production due to inflammatory cytokines, released by activated macrophagesHigher levels associated with: ↑Severity, ↑Mortality

      High levels are indicators ofCSS/sHLH development
      (1, 2, 6, 5)
      ProcalcitoninIncreased production due to inflammatory cytokinesHigher levels associated with: ↑Severity, ↑Mortality, Bacterial superinfections(4, 3, 18, 2, 6, 5, 19)
      Serum amyloid AIncreased production due to inflammatory cytokinesHigh levels seen among: all COVID-19 patients(3)
      Biochemistry indices
      CholinesteraseUnknown exact mechanismLower levels associated with:

      ↑ Severity
      (53)
      Electrolytes (Na, K, Cl)Multiple mechanisms (e.g. SIADH, acidosis etc.)No clear association with disease severity and outcomes(1, 11, 18, 51)
      Lactate dehydrogenase (LDH)Released by cell injuryHigher levels associated with: ↑Severity, ↑Mortality, Lack of improvement

      High levels on admission may be used as prognostic marker for severity
      (11, 2, 1, 6, 5, 19, 16)
      TriglyceridesReduced lipoprotein lipase activity due to high TNF-α levelsHigher levels have been reported in fatal cases but not enough data

      Component of HScore for CSS/sHLH diagnosis
      (1)
      TSH/FT3Possible euthyroid sick syndrome of critical illnessHigher levels have been reported in fatal cases, not enough data(1)
      Cardiac biomarkers
      Hs-troponin IReleased by myocardial injuryHigher levels associated with:↑igher levels associa, lack of improvement

      High levels on admission or gradual increase may be used as prognostic marker for severity and mortality
      (54, 31, 33, 4)
      Troponin TReleased by myocardial injuryHigher levels associated with:

      ↑igher levels associa
      (32)
      CK-MBReleased by myocardial injuryHigher levels associated with:↑igher le(33, 4)
      NT-proBNPIncreased production due to heart failureHigher levels associated with:↑igher le(31, 33)
      Renal function indices
      CreatinineDecreased discharge due to renal injuryHigher levels associated with:

      ↑igher levels associa
      (4, 2, 55, 34, 31)
      BUNDecreased discharge due to renal injuryHigher levels associated with:

      ↑igher levels associa
      (31, 34, 55, 4)
      Urinary proteinPossiblypositive due to renal dysfunctionProteinuria may associated with:↑roteinuri (limited data)(34)
      Urinary erythrocytePossibly positive due to renal dysfunctionHematuria may associated with:↑ematuria (limited data)(34)
      Liver function indices
      ALTPossibly liver injury, unknown exact mechanismHigher levels associated with:

      ↑igherity, (↑Mortality, indeterminate data)
      (2, 31, 4, 18, 36)
      ASTPossibly myocardial or liver injury, unknown exact mechanismHigher levels associated with:

      ↑igher leve(↑Mortality, indeterminate data)
      (31, 4, 18, 36)
      TBILUnknown exact mechanismHigher levels associated with:

      ↑igher le
      (36, 31)
      GGTUnknown exact mechanismHigher levels associated with:

      ↑igher le (limited data)
      (36)
      ALPIncreased levels in some patients, unknown exact mechanismNo clear association with disease severity and outcomes(36, 56)
      Coagulation profile
      D-dimerElevated levels possibly due to hypercoagulability and secondary fibrinolysisHigher levels associated with:

      ↑igher levels associa

      D-dimer>1 ng/mlon admission or gradual increase may be used as prognostic marker for severity and mortality
      (4, 3, 2, 55, 31)
      PTProlonged PT possibly duehypercoagulability and secondary fibrinolysisHigher levels associated with:

      ↑igher lev
      (2, 4, 55, 44, 57)
      INRElevated levels possibly duehypercoagulability and secondary fibrinolysisHigher levels may associated with:↑Severity (limited data)(36)
      APTTUnknown exact mechanismIndeterminate association with disease severity and outcomes(44, 5, 55)
      FibrinogenElevated as an acute phase protein and may decreasedue to hypercoagulabilityHigher levels may associated with:↑igher levels may ass (limited data)(44, 43)
      Cytokines and chemokines
      IL-1βIncreased production/Associated with CSS/sHLHHigher levels may be associated with: ↑Mortality

      Indeterminate data for severity
      (58, 1, 6, 11, 10)
      IL-2/ soluble IL-2RIncreased production/Associated with CSS/sHLHHigher levels associated with: ↑Severity, ↑Mortality(58, 1, 11, 6, 10)
      IL-6Increased production/Associated with CSS/sHLHHigher levels associated with: ↑Severity, ↑Mortality

      IL-6 levels may monitor disease progression

      Higher of IL-6 to IFN-γ ratio may distinguish severe from moderate cases
      (5, 24, 58, 1, 11, 6, 2, 10)
      IL-7Increased production/Associated with CSS/sHLHHigher levels associated with: ↑Severity(58, 11)
      IL-8Increased production/Associated with CSS/sHLHHigher levels may be associated with:↑Severity(Indeterminate data)(6, 10)
      IL-10Increased production by macrophagesHigher levels associated with: ↑Severity (also ↑Mortality, but not enough data)(58, 1, 11, 6)
      IL-17Increased production/Associated with CSS/sHLHHigher levels may be associated with:↑Severity (Not enough data)(10)
      IP10 (CXCL10)Increased production/Associated with CSS/sHLHHigher levels associated with: ↑Severity(58, 11)
      G-CSF/GM-CSFIncreased production/Associated with CSS/sHLHHigher levels associated with: ↑Severity(58, 11, 10)
      TNF-αIncreased production/Associated with CSS/sHLHHigher levels associated with: ↑Severity(also ↑Mortality, but not enough data)(58, 1, 11, 6, 10)
      MCP1 (CCL2)Increased production/Associated with CSS/sHLHHigher levels associated with: ↑Severity(58, 11, 10)
      MIP-1α (CCL3)Increased production/Associated with CSS/sHLHHigher levels associated with: ↑Severity(58, 11, 6, 10)
      INF-γReduced production by CD4+ T cellsLower levels may be associated with: ↑Severity

      Higher of IL-6 to IFN-γratio may distinguish severe from moderate cases
      (24, 11, 58, 6)
      ComplementPossible activation of the alternative and lectin-based complement pathways from viral proteinsDeposits of C5b-9, C4d and MASP 2 in the microvasculature of lungs (from autopsy specimens)

      No differences in C3/C4 levels among survivors- non survivors
      (1, 27, 59)
      Immunoglobulins (IgA, IgG, IgM)In theory, increased production induced by activated B-cellsNo differences in IgA/IgG/IgM levels among survivors- non survivors(1)
      Soluble urokinase plasminogen activator receptor (suPAR)Increased due to endothelial activationHigh levels may be associated with: prediction of respiratory failure(
      • Rovina N.
      • Akinosoglou K.
      • Eugen-Olsen J.
      • et al.
      Soluble urokinase plasminogen activator receptor (suPAR) as an early predictor of severe respiratory failure in patients with COVID-19 pneumonia.
      )
      Arterial blood gases parameters
      pHRespiratory alkalosis driven by hypoxemia, metabolic acidosis due organ hypoperfusionConflicting data on pH and associated mortality. One study found statistically higher frequency of acidosis among fatal cases(1, 2)
      BicarbonatesDecreased due to respiratory alkalosis and metabolic acidosisNot enough data – possibly lower among non-survivors(1)
      PaO2Decreased due to alveolar and microvasculature injury (direct and indirect)Frequency of type I respiratory failure is significantly higher among non survivors

      Markedly low PaO2 (<60 mmHg) levels are seen in fatal cases
      (1, 2)
      PaCO2Decreased due to high respiratory rate driven by hopoxia/shuntNot enough data – possibly lower among non-survivors(1)
      PaO2:FiO2 ratioDecreased due to alveolar and microvasculature injury (direct and indirect)PaO2:FiO2 ratio of ≤300 associated with ↑Mortality(1)
      Cl: Chloride, CSS/sHLH: Cytokine storm syndrome/secondary Hemophagocytic lymphohistiocytosis, FiO2: Fraction of inspired oxygen, FT3: Free triiodothyronine, G-CSF: Granulocyte-colony stimulating factor, GM-CSF: Granulocyte-macrophage colony-stimulating factor, IL: Interleukin, IP10:Interferon gamma-induced protein 10, K: Potassium, MASP 2: mannose binding lectin associated serine protease 2. MCP1 (CCL2): Monocyte chemoattractant protein 1, MIP-1α (CCL3): Macrophage inflammatory protein 1-alpha), Na: Sodium,PaCO2:Arterial carbon dioxide partial pressure, PaO2: Arterial oxygen partial pressure, SIADH: Syndrome of inappropriate antidiuretic hormone secretion, soluble IL-2R: soluble Interleukin 2 receptor, TSH: Thyroid stimulating hormone, BUN, blood urea nitrogen; ALT, alanine transaminase; AST, aspartate transaminase; TBIL, total bilirubin; GGT,gamma-glutamyl transpeptidase; ALP, alkaline phosphatase; CK-MB, creatine kinase MB; PT, prothrombin time; APTT, activated partial thromboplastin time; INR, international normalized ratio; Hs-troponin I, high sensitivity troponin I.
      Table 2Laboratory parameters in pediatric COVID-19 patients.
      BIOMARKERPEDIATRIC COVID-19 DATAREFERENCES
      Hematological indices
      HemoglobinPotentially similar to adults(52, 53)
      LymphocytesHigher lymphocyte counts compared to adults

      Normal lymphocyte counts common

      Lymphopenia in 0–35% of children

      Lymphocytosis is rare
      (52, 54–57)
      Total white blood cells/NeutrophilsHigher levels associated with:

      Symptomatic disease, Younger age (<2 y.o.)

      Lower neutrophil counts compared to adults

      Leukocytosis is more frequent

      Leukopenia is rare
      (52, 55–57)
      Acute phase reactants
      AlbuminLess frequently decreased compared to adults(57, 53)
      C-reactive protein (CRP)Lower CRP levels compared to adults

      High CRP in 10%−83% of children
      (52, 55, 56)
      Erythrocyte sedimentation rateLess frequently elevated compared to adults(57)
      ProcalcitoninCan be high in hospitalized children

      More frequently elevated compared to adults
      (56, 57)
      Biochemistry indices
      Lactate dehydrogenase (LDH)Normal LDH levels commonly

      Higher LDH levels compared to adults in one report
      (52, 55, 57)
      Cytokines and chemokines
      IL-6Lower IL-6 levels compared to adults(52)

      Hemoglobin and white blood cells

      Retrospective analyses from China demonstrated that leukocyte counts were higher among non-survivors compared to recovered patients
      • Chen T.
      • Wu Di
      • Chen H.
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      Clinical characteristics of 113 deceased patients with coronavirus disease 2019, retrospective study.
      ,
      • Zhou F.
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      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China, a retrospective cohort study.
      ; in particular, Zhou et al. reported that COVID-19 patients who did not survive had a median of 9.8 × 109/L WBC count compared to 5.2 × 109/L among those who survived (p<0.0001), although the exact time point of measurement was not defined in their methods. Furthermore, another study of 140 hospitalized patients in Wuhan, demonstrated significantly higher leukocyte counts among those with severe COVID-19 disease, compared to patients with milder infection (p = 0.003).
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      Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China.
      Finally, a series from the same center, and possibly overlapped populations with the previous study, reported significantly higher WBC counts upon hospital admission among patients requiring critical care, although median values were within normal range (WBC count median 6.6 × 109/L for ICU vs 4.3 × 109/L for non-ICU admission, p = 0.003).
      • Wang D.
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      • Hu C.
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      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.
      The observed leukocytosis is attributed to an elevation of neutrophils, as the other WBC populations seem to drop in severely ill and eventually fatal COVID-19 cases.
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      Absolute lymphopenia is commonly observed in patients with COVID-19, but pronounced lymphocyte depletion is a cardinal marker of enhanced disease severity and an indicator of imminent death, that has been consistently depicted by almost all currently published reports, coming mainly from China.
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      Clinical characteristics of 113 deceased patients with coronavirus disease 2019, retrospective study.
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      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China, a retrospective cohort study.
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      Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China.
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      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.
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      Hematologic parameters in patients with COVID-19 infection.
      Importantly, not only the degree of lymphocyte drop, but also the persistence of low lymphocyte counts throughout the disease course have been associated with critical illness and death.
      • Chen T.
      • Wu Di
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      Clinical characteristics of 113 deceased patients with coronavirus disease 2019, retrospective study.
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      • Zhou F.
      • Yu T.
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      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China, a retrospective cohort study.
      ,
      • Wang D.
      • Hu B.
      • Hu C.
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      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.
      In contrast to previous reports for SARS-CoV, peripheral blood smears reveal the presence of reactive lymphocytes, including some lymphoplasmacytoids, in the majority of COVID-19 patients
      • Fan B.E.
      • Chong V.C.L.
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      Hematologic parameters in patients with COVID-19 infection.
      • Chng W.J.
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      Haematological parameters in severe acute respiratory syndrome.
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      A major outbreak of severe acute respiratory syndrome in Hong Kong.
      . Severe SARS-CoV-2 infection depletes all lymphocyte subsets, including CD4+ T cells, CD8+ T cells, B cells and natural killer (NK) cells, but CD4+/ CD8+ ratio is not inverted as seen in other viral infections.
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      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
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      Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
      • Qin C.
      • Zhou L.
      • Hu Z.
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      Dysregulation of immune response in patients with COVID-19 in Wuhan, China.
      Not only the absolute numbers of T-cells are reduced, but also receptors suppressing their cytotoxic effects, like the CD94/NKG2A receptor, are up-regulated leading to diminished defense mechanisms against the virus.
      • Cao X
      COVID-19, Immunopathology and its implications for therapy.
      Monocyte, eosinophil and basophil counts are also decreased in COVID-19, but the magnitude of this reduction has not been associated with disease severity, in currently published data from Chinese centers.
      • Zhang J.-.J.
      • Dong X.
      • Cao Y.-.Y.
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      Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China.
      ,
      • Cao X
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      ,

      Zhang B., Zhou X., Zhu C., et al. Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19, 2020.

      Moreover, pro-inflammatory cytokines are known to blunt erythropoiesis.
      • Nemeth E.
      • Ganz T.
      Anemia of inflammation.
      However, aside from one study that found significantly higher frequencies of decreased hemoglobin concentrations among severe (43.6%) and critical cases (37.2%) compared to mild/moderate ones (23.1%) (p<0.001), solid evidence of significant hemoglobin reduction in severe COVID-19 has not been consistently reported as yet.
      • Henry B.M.
      • Oliveira MHS de
      • Benoit S.
      • Plebani M.
      • Lippi G
      Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19), A meta-analysis.
      ,
      • Huang C.
      • Wang Y.
      • Li X.
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      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Zhang J.
      • Wang X.
      • Jia X.
      • et al.
      Risk factors for disease severity, unimprovement, and mortality of COVID-19 patients in Wuhan, China.
      In one particular study, lower hemoglobin concentration was associated with increased odds for lack of disease improvement but not death (odds ratio 1.731, p = 0.008).
      • Zhang J.
      • Wang X.
      • Jia X.
      • et al.
      Risk factors for disease severity, unimprovement, and mortality of COVID-19 patients in Wuhan, China.
      Preliminary reports imply that high neutrophil counts and persistently deep lymphocyte nadir counts during hospitalization as well as high neutrophil to lymphocyte ratios (NLR) are indicators of adverse outcomes such as ICU admission and death
      • Cao X
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      . A retrospective Chinese study reported that NLR, along with the SARS-CoV-2 IgG levels, could be used as a simple discriminative tool for severity between COVID-19 patients, and further predict the clinical outcome of these patients

      Zhang B., Zhou X., Zhu C., et al. Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19, 2020.

      . However, whether these indices can actually risk stratify patients and predict poor outcomes, most importantly at an early stage of the disease, remains to be addressed and validated in large prospective trials.

      Common inflammatory markers – Acute phase reactants

      The regulation of ferritin synthesis is cytokine-controlled
      • Kernan K.F.
      • Carcillo J.A
      Hyperferritinemia and inflammation.
      ; hence, the extreme immune activation in the context of the cytokine storm observed in critical, and usually fatal, cases of COVID-19, leads to an up-regulation of serum ferritin levels. Indeed, preliminary patient data demonstrate that excessive ferritin levels are observed among COVID-19 patients, ranging from 400 μg/L to as high as >2000 μg/L, with the highest trends being observed in severe cases and in non-survivors.
      • Chen T.
      • Wu Di
      • Chen H.
      • et al.
      Clinical characteristics of 113 deceased patients with coronavirus disease 2019, retrospective study.
      ,
      • 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.
      ,
      • Chen G.
      • Wu Di
      • Guo W.
      • et al.
      Clinical and immunological features of severe and moderate coronavirus disease 2019.
      Direct correlation between serum ferritin concentration and poor survival, as reported by the meta-analysis conducted by Henry et al. (weighted mean difference: 408.28 μg/L, 95%CI: 311.12–505.44 μg/L, Cochran's Q p-value=0.01), suggests its use as a surrogate marker of immune dysregulation and a prognostic marker of disease severity and imminent death.
      • Henry B.M.
      • Oliveira MHS de
      • Benoit S.
      • Plebani M.
      • Lippi G
      Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19), A meta-analysis.
      Only scarce data have contextualized the erythrocyte sedimentation rate (ESR) kinetic in patients with COVID-19. One study reported that fatal cases had a tendency for higher ESR compared to those who recovered (median ESR 38.5 vs 28 mm/h) without reporting the statistical significance of the observed difference among the two groups.
      • Chen T.
      • Wu Di
      • Chen H.
      • et al.
      Clinical characteristics of 113 deceased patients with coronavirus disease 2019, retrospective study.
      A similar trend was also depicted for C-reactive protein (CRP) concentration by the same study, with median levels being 4-fold higher among non-survivors (median concentration 113 vs 26.2 mg/L).
      • Chen T.
      • Wu Di
      • Chen H.
      • et al.
      Clinical characteristics of 113 deceased patients with coronavirus disease 2019, retrospective study.
      Between severe and non-severe cases, reported CRP differences are not that striking (median (IQR): 47.6 mg/L (20.6–87.1) vs 28.7 mg/L (9.5–52.1), p<0.001), but significantly increased frequency of higher concentrations among severe and critical cases compared to mild/moderate ones are nevertheless evident (mild/moderate cases: 50.5%, severe cases: 79.2% and critical cases: 92%, p<0.001).
      • Zhang J.-.J.
      • Dong X.
      • Cao Y.-.Y.
      • et al.
      Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China.
      ,
      • Zhang J.
      • Wang X.
      • Jia X.
      • et al.
      Risk factors for disease severity, unimprovement, and mortality of COVID-19 patients in Wuhan, China.
      Finally, one Chinese study with 663 COVID-19 patients reported that higher CRP levels are inversely associated with disease improvement (odds ratio 4.697, p<0.0001).
      • Zhang J.
      • Wang X.
      • Jia X.
      • et al.
      Risk factors for disease severity, unimprovement, and mortality of COVID-19 patients in Wuhan, China.
      Individual studies demonstrate that greater procalcitonin (PCT) concentrations (usually ≥0.05 ng/ml) can significantly distinguish between non-severely from severely ill and fatal cases, thus possibly acting as a prognostic marker.
      • 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.
      • Zhang J.-.J.
      • Dong X.
      • Cao Y.-.Y.
      • et al.
      Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China.
      • Wang D.
      • Hu B.
      • Hu C.
      • et al.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.
      ,
      • Chen G.
      • Wu Di
      • Guo W.
      • et al.
      Clinical and immunological features of severe and moderate coronavirus disease 2019.
      ,
      • Guan W.-.J.
      • Ni Z.-.Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Gong J.
      • Ou J.
      • Qiu X.
      • et al.
      A tool to early predict severe corona virus disease 2019 (COVID-19), a multicenter study using the risk nomogram in Wuhan and Guangdong, China.
      However, a meta-analysis found that severe from non-severe COVID-19 could be differentiated by a marginally higher PCT (by 0.2 ng/ml).
      • Henry B.M.
      • Oliveira MHS de
      • Benoit S.
      • Plebani M.
      • Lippi G
      Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19), A meta-analysis.
      Increments of both CRP and PCT may be associated, not only with the immense inflammatory response, but also with the higher frequency of bacterial superinfections among critically ill COVID-19 patients (up to 50% rate among non-survivors).
      • Henry B.M.
      • Oliveira MHS de
      • Benoit S.
      • Plebani M.
      • Lippi G
      Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19), A meta-analysis.
      The differentiation between severe SARS-CoV-2 infection and a bacterial superinfection is often difficult in clinical practice. Though markedly elevated PCT and CRP are consistent with bacterial co-infection, there is not a clear cut-off. Other markers that have been proposed as differentiators between bacterial and viral infections (such as Myxoma resistance protein (MxA1), Lipocalin 2 (Lcn2), High mobility group box one protein (HMGB1)) have not been studied in COVID-19 disease.
      • Thomas J.
      • Pociute A.
      • Kevalas R.
      • Malinauskas M.
      • Jankauskaite L
      Blood biomarkers differentiating viral versus bacterial pneumonia aetiology, A literature review.
      Albumin is a negative acute phase reactant whose synthesis is down-regulated by inflammatory cytokines.
      • Gulhar R.
      • Ashraf M.A.
      • StatPearls I.Jialal
      Physiology, Acute Phase Reactants.
      Therefore, it is not surprising that hypoalbuminemia (usually <30 g/L) has been persistently noticed among patients with severe or fatal COVID-191,2,6,11. Moreover, one study demonstrated that low albumin concentration was associated with lack of disease improvement (odds ratio 2.377, p<0.0001), while hypoalbuminemia was also introduced as a risk factor, among other parameters, in a proposed risk prediction nomogram for severe COVID-19.16,19
      Serum amyloid A (SAA) is another acute phase reactant inhibiting monocyte mobilization, platelet activation and various chemotactic pathways.
      • Gulhar R.
      • Ashraf M.A.
      • StatPearls I.Jialal
      Physiology, Acute Phase Reactants.
      High concentrations of SAA among all COVID-19 patients have only been reported by Zang et al., without a significant difference between severe and non-severe cases.
      • Zhang J.-.J.
      • Dong X.
      • Cao Y.-.Y.
      • et al.
      Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China.

      Cytokines, chemokines, pathology findings and other markers

      Exuberant release of pro-inflammatory cytokines is associated with multi-organ injury and acute respiratory distress syndrome (ARDS), which is inevitably fatal if left untreated.
      • Mehta P.
      • McAuley D.F.
      • Brown M.
      • Sanchez E.
      • Tattersall R.S.
      • Manson J.J
      COVID-19, consider cytokine storm syndromes and immunosuppression.
      Fulminant hypercytokinemia has been increasingly recognized among critically ill COVID-19 patients.
      Distinct pro-inflammatory cytokines (such as interleukin (IL)−1β, IL-2 and its soluble receptor, IL-6, IL-8, IL-17, Granulocyte colony-stimulating factor (G-CSF), Granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor alpha (TNF-α)), inflammatory chemokines (such as the monocyte chemoattractant protein 1 (MCP1or CCL2) and the macrophage inflammatory protein 1-alpha (MIP-1α or CCL3)), as well as the anti-inflammatory cytokine IL-10, have been consistently found significantly elevated in patients with severe COVID-19, those admitted to ICU or patients who died compared to milder forms of SARS-CoV-2 infection.
      • Chen T.
      • Wu Di
      • Chen H.
      • et al.
      Clinical characteristics of 113 deceased patients with coronavirus disease 2019, retrospective study.
      ,
      • 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.
      ,
      • Chen G.
      • Wu Di
      • Guo W.
      • et al.
      Clinical and immunological features of severe and moderate coronavirus disease 2019.
      ,
      • Cao X
      COVID-19, Immunopathology and its implications for therapy.
      ,
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Wu D.
      • Yang X.O.
      TH17 responses in cytokine storm of COVID-19, An emerging target of JAK2 inhibitor Fedratinib.
      Notably, monitoring of IL-6 levels has been proposed as a candidate index for disease progression.
      • Henry B.M.
      • Oliveira MHS de
      • Benoit S.
      • Plebani M.
      • Lippi G
      Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19), A meta-analysis.
      Moreover, higher of IL-6 to Interferon gamma (IFN-γ) ratios may distinguish severe from moderate COVID-19 cases (standardized mean difference of 0.739, 95% CI = 0.131–1.383).
      • Lagunas-Rangel F.A.
      • Chávez-Valencia V.
      High IL-6/IFN-γ ratio could be associated with severe disease in COVID-19 patients.
      All these data converge into the conclusion that major immune dysregulation occurs in severe COVID-19, leading to many clinical manifestations of the fatal form. Although measurement of these indices is not widely available, following up such markers may be an integral part of relevant prognostic and diagnostic tools.
      On the other hand, complement components C3 and C4 and immunoglobulin (IgG, IgM and IgA) levels are not specific markers of the cytokine storm syndrome and the few data that are available showed no clinically significant differences between deceased and recovered patients
      • Chen T.
      • Wu Di
      • Chen H.
      • et al.
      Clinical characteristics of 113 deceased patients with coronavirus disease 2019, retrospective study.
      . However, exuberant SARS-CoV-2-specific IgG responses were associated with increased disease severity, in a retrospective Chinese study with 222 COVID-19 patients.

      Zhang B., Zhou X., Zhu C., et al. Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19, 2020.

      Cytokine storm can certainly, but only partially, explain the observed clinical features of COVID-19 disease. Angiotensin-converting enzyme 2 (ACE2) receptors, the mediators of SARS-CoV-2 invasion into host-cells, are expressed by numerous cells, including endothelium; therefore, direct viral endothelial injury cannot be excluded.
      • Ferrario C.M.
      • Jessup J.
      • Chappell M.C.
      • et al.
      Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2.
      Indeed, preliminary histopathological data from fatal cases demonstrated lesions consistent with endotheliitis (endothelialitis) in many organs including lungs, small lung vessels’ congestion, mononuclear cell infiltrates within the intima of organs’ vasculature, viral inclusion bodies in peritubular spaces and viral particles in endothelial cells of the glomerular capillary loops.
      • Varga Z.
      • Flammer A.J.
      • Steiger P.
      • et al.
      Endothelial cell infection and endotheliitis in COVID-19.
      Another series reported the identification of C5b-9, C4d and mannose binding lectin-associated serine protease (MASP) 2 terminal complement component deposits in pulmonary microvasculature; furthermore, co-localization of spike glycoproteins with C4d and C5b-9 in inter-alveolar septa and on skin microvasculature were evident is some cases.
      • Magro C.
      • Mulvey J.J.
      • Berlin D.
      • et al.
      Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection, A report of five cases.
      This observation is consistent with a systemic complement activation leading to a catastrophic pauci-inflammatory septal capillary injury and a pro-coagulant state.
      • Magro C.
      • Mulvey J.J.
      • Berlin D.
      • et al.
      Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection, A report of five cases.
      Importantly, hallmarks of classic ARDS such as typical diffuse alveolar damage (DAD) were not prominent.
      • Magro C.
      • Mulvey J.J.
      • Berlin D.
      • et al.
      Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection, A report of five cases.
      Moreover, the connection of viral spike protein to ACE2 receptor, down-regulates ACE2 levels in lungs; this in turn, increases the angiotensin II (AngII) levels, reduces angiotensin 1–7 (Ang-(1–7)), and imbalances the renin-angiotensin system in the lung, leading to vasoconstriction.
      • Li S.-.R.
      • Tang Z.-.J.
      • Li Z.-.H.
      • Liu X
      Searching therapeutic strategy of new coronavirus pneumonia from angiotensin-converting enzyme 2, The target of COVID-19 and SARS-CoV.
      These data are in concordance with a notably distinct type of ARDS with highly compliant lungs, which is seen in a major subset of COVID-19 patients; this manifestation is quite possibly consistent with an underlying vasoconstriction and microvasculature injury leading to loss of lung perfusion regulation
      • Gattinoni L.
      • Coppola S.
      • Cressoni M.
      • Busana M.
      • Rossi S.
      • Chiumello D
      Covid-19 does not lead to a "Typical" acute respiratory distress syndrome.
      . Though neither histopathology specimens nor lung ACE2 or AngII levels are easily obtainable in daily clinical practice, they would definitely be useful in research settings in order to elucidate the disease's pathophysiology and may assist diagnosis in the future.

      Cardiac biomarkers

      Cardiac troponin I and T are highly sensitive and specific biomarkers of myocardial injury which can be caused by myocardial ischemia, inflammation, immune response, and toxin.
      • Mair J.
      • Lindahl B.
      • Hammarsten O.
      • et al.
      How is cardiac troponin released from injured myocardium?.
      Elevated troponin at admission was observed in more than half of dead patients and associated with increased severity and mortality in COVID-19 patients.
      • Chen T.
      • Wu Di
      • Chen H.
      • et al.
      Clinical characteristics of 113 deceased patients with coronavirus disease 2019, retrospective study.
      ,
      • 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.
      ,
      • Li X.
      • Xu S.
      • Yu M.
      • et al.
      Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan.
      Regardless of underlying cardiovascular disease, patients with dynamic increases of troponin during the hospitalization were more likely to have fatal outcomes.
      • 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.
      ,
      • Li X.
      • Xu S.
      • Yu M.
      • et al.
      Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan.
      • Guo T.
      • Fan Y.
      • Chen M.
      • et al.
      Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19).
      • Deng Q.
      • Hu B.
      • Zhang Y.
      • et al.
      Suspected myocardial injury in patients with COVID-19, Evidence from front-line clinical observation in Wuhan, China.
      Although some COVID-19 patients were reported with comorbidity of chronic heart disease, the underlying mechanism for troponin elevation in patients with COVID-19 is not clear. The myocardial injury in COVID-19 patients might associate with a systemic hyperinflammation
      • Qin C.
      • Zhou L.
      • Hu Z.
      • et al.
      Dysregulation of immune response in patients with COVID-19 in Wuhan, China.
      ,
      • Li X.
      • Xu S.
      • Yu M.
      • et al.
      Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan.
      rather than a virus attack directly. Increased levels of CK-MB and NT-proBNP can also be found in severe COVID-19 patients compared to non-severe patients.
      • Wang D.
      • Hu B.
      • Hu C.
      • et al.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.
      ,
      • Li X.
      • Xu S.
      • Yu M.
      • et al.
      Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan.
      ,
      • Deng Q.
      • Hu B.
      • Zhang Y.
      • et al.
      Suspected myocardial injury in patients with COVID-19, Evidence from front-line clinical observation in Wuhan, China.

      Renal function tests

      According to a cohort study
      • Cheng Y.
      • Luo R.
      • Wang K.
      • et al.
      Kidney disease is associated with in-hospital death of patients with COVID-19.
      of 701 patients with COVID-19, the proportion of proteinuria, hematuria, abnormal serum creatinine and urea nitrogen at admission and were 43.9, 26.7, 14.4 and 13.1%, respectively. In addition, there was a high prevalence (5.1%) of acute kidney injury (AKI) during the study period. The result showed proteinuria, hematuria, and elevated serum creatinine/urea nitrogen at admission and acute kidney injury (AKI) during hospitalization over stage 2 were associated with in-hospital death. However, the other largest retrospective study to date found that the prevalence of serum creatinine abnormalities and AKI was only 1.6% and 0.5%.
      • Guan W.-.J.
      • Ni Z.-.Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      This may be due to the different proportions of severe patients between the two studies and the different definitions of the normal reference range for serum creatinine. From the result of autopsy of 26 COVID-19 patients,
      • Su H.
      • Yang M.
      • Wan C.
      • et al.
      Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China.
      the histopathology of the kidney revealed significant acute tubular injury and found that the tubular epithelial cells were directly infected by SARS-CoV2. Therefore, SARS-CoV2 may cause kidney injury or exacerbate existing kidney disease. Attention should be paid to monitoring renal function and the occurrence of AKI.

      Liver function tests

      Abnormal liver function tests, such as increased levels of ALT, AST, TBIL, GGT and decreased level of albumin were relatively common in patients with COVID-19, and 10–33% of these patients had abnormal ALT or AST.
      • 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.
      ,
      • Wang D.
      • Hu B.
      • Hu C.
      • et al.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.
      ,
      • Guan W.-.J.
      • Ni Z.-.Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Li X.
      • Xu S.
      • Yu M.
      • et al.
      Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan.
      ,
      • Zhang Y.
      • Zheng L.
      • Liu L.
      • Zhao M.
      • Xiao J.
      • Zhao Q
      Liver impairment in COVID-19 patients, A retrospective analysis of 115 cases from a single center in Wuhan city, China.
      Although patients with severe COVID-19 seem to have higher rates of liver dysfunction, it is reassuring that the levels of ALT, AST, TBIL, GGT in COVID-19 patients were not significantly different in compared with hospitalized community-acquired pneumonia patients and even the median or average transaminase level in severe COVID-19 patients was lower than twice upper reference limit.
      • Wang D.
      • Hu B.
      • Hu C.
      • et al.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.
      ,
      • Zhang Y.
      • Zheng L.
      • Liu L.
      • Zhao M.
      • Xiao J.
      • Zhao Q
      Liver impairment in COVID-19 patients, A retrospective analysis of 115 cases from a single center in Wuhan city, China.
      ,
      • Bangash M.N.
      • Patel J.
      • Parekh D
      COVID-19 and thE liver, Little cause for concern.
      Therefore, the clinical effect of these elevated indicators may not be evident in COVID-19 patients. Liver dysfunction may be related to severe infection, inflammation induced liver injury, medication associated hepatotoxicity and hypoxia.
      • Zhang C.
      • Shi L.
      • Wang F.-.S
      Liver injury in COVID-19, Management and challenges.

      Coagulation profile

      D-dimer is a degradation product of fibrin. Elevated D-dimer levels were consistently reported in COVID-19 patients with prevalence ranging from 43 to 68%.
      • 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.
      ,
      • Zhang J.-.J.
      • Dong X.
      • Cao Y.-.Y.
      • et al.
      Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China.
      ,
      • Li X.
      • Xu S.
      • Yu M.
      • et al.
      Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan.
      D-dimer>1 ng/ml at admission were associated with increased severity and odds of death with COVID-19, and the gradual increasing of D-dimer during disease course was particularly associated with disease worsening and mortality.
      • 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.
      ,
      • Wang D.
      • Hu B.
      • Hu C.
      • et al.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.
      Serum D-dimer can reflect fibrinolytic activities and is also an inflammatory biomarker. Furtherly, recent studies found that severe cases of COVID-19 were commonly complicated with thrombosis,
      • Klok F.A.
      • Kruip M.J.H.A.
      • van der Meer N.J.M.
      • et al.
      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
      ,
      • Tavazzi G.
      • Civardi L.
      • Caneva L.
      • Mongodi S.
      • Mojoli F
      Thrombotic events in SARS-CoV-2 patients, An urgent call for ultrasound screening.
      markedly elevated D-dimer was related to thrombosis and poor prognosis of severe COVID-19 patients. Prothrombin time (PT) reflects the activity of exogenous coagulation factors. COVID-19 associated lung tissue damage may induce the release of tissue factors to circulation and promotes secondary fibrinolysis through exogenous coagulation pathways. This may explain the elevated D-dimer and prolonged PT in COVID-19 as well as CAP patients.
      • 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.
      ,
      • Wang D.
      • Hu B.
      • Hu C.
      • et al.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.
      ,
      • Guan W.-.J.
      • Ni Z.-.Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Li X.
      • Xu S.
      • Yu M.
      • et al.
      Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan.
      ,
      • Zhang Y.
      • Zheng L.
      • Liu L.
      • Zhao M.
      • Xiao J.
      • Zhao Q
      Liver impairment in COVID-19 patients, A retrospective analysis of 115 cases from a single center in Wuhan city, China.
      The fibrinogen is a kind of coagulation factor, but also an acute phase protein
      • Fish R.J.
      • Neerman-Arbez M
      Fibrinogen gene regulation.
      . It can be induced by infection or other stress factors.
      • Amaral A.
      • Opal S.M.
      • Vincent J.-.L
      Coagulation in sepsis.
      Several literatures reported fibrinogen levels was elevated in severe patients or non-survivors with COVID-19.
      • Feng Y.
      • Ling Y.
      • Bai T.
      • et al.
      COVID-19 with different severity, a multi-center study of clinical features.
      ,
      • Tang N.
      • Li D.
      • Wang X.
      • Sun Z
      Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
      However, Du et al. found fibrinogen increased in 47.1% of fatal cases and decreased in 22.4% of fatal cases.
      • Du Y.
      • Tu L.
      • Zhu P.
      • et al.
      Clinical features of 85 fatal cases of COVID-19 from Wuhan, a retrospective observational study.
      In fact, the fibrinogen would decrease when excessive consumption happened due to hypercoagulability or the worst disseminated intravascular coagulation occurred. Hence, the abnormality of the coagulation profile should be interpreted individually.

      Biochemistry markers and arterial blood gases

      Lactate dehydrogenase (LDH) is a cytoplasmic enzyme that is present in every tissue, and high serum concentrations indicate underlying organ damage. Thus, LDH is expected to rise in severe COVID-19 cases, where multi-organ damage occurs.
      • Wu D.
      • Yang X.O.
      TH17 responses in cytokine storm of COVID-19, An emerging target of JAK2 inhibitor Fedratinib.
      Current data support that critically ill patients as well as fatal cases of COVID-19 have significantly higher LDH levels (usually >320 U/L) compared to moderate infections.
      • Chen T.
      • Wu Di
      • Chen H.
      • et al.
      Clinical characteristics of 113 deceased patients with coronavirus disease 2019, retrospective study.
      ,
      • 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.
      ,
      • Henry B.M.
      • Oliveira MHS de
      • Benoit S.
      • Plebani M.
      • Lippi G
      Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19), A meta-analysis.
      ,
      • Chen G.
      • Wu Di
      • Guo W.
      • et al.
      Clinical and immunological features of severe and moderate coronavirus disease 2019.
      ,
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Zhang J.
      • Wang X.
      • Jia X.
      • et al.
      Risk factors for disease severity, unimprovement, and mortality of COVID-19 patients in Wuhan, China.
      Moreover, higher LDH quadruples the odds for lack of disease improvement (odds ratio: 4.381. p<0.0001).
      • Zhang J.
      • Wang X.
      • Jia X.
      • et al.
      Risk factors for disease severity, unimprovement, and mortality of COVID-19 patients in Wuhan, China.
      Lastly, greater LDH concentrations upon admission correlate with a higher risk for serious COVID-19, and therefore it has been added in a proposed early predictive tool for severe infection.
      • Gong J.
      • Ou J.
      • Qiu X.
      • et al.
      A tool to early predict severe corona virus disease 2019 (COVID-19), a multicenter study using the risk nomogram in Wuhan and Guangdong, China.
      These data favor the utilization of LDH as a candidate prognostic marker for disease severity.
      Hypertriglyceridemia is commonly encountered in hyperinflammatory states, like the CSS and the secondary HLH, due to the reduced lipoprotein lipase activity driven by the high TNF-α levels.
      • George M.R
      Hemophagocytic lymphohistiocytosis, Review of etiologies and management.
      Therefore, triglyceride concentration is a key component of the HScore [http://saintantoine.aphp.fr/score/] that is currently being proposed by the European Society of Intensive Care Medicine as a predictive tool for SARS-CoV-2-driven sHLH in COVID-1922,

      ESICM. Important Announcement of new SSC Guidelines – COVID-19. (Accessed April 27, 2020, at https://www.esicm.org/ssc-covid19-guidelines/).

      However, only scarce data on triglycerides levels in COVID-19 disease are currently available; one study reported higher concentrations in fatal cases as compared to patients who survived the disease (median 1.8 vs 1.2 mmol/L), without stating the statistical significance of this finding
      • Chen T.
      • Wu Di
      • Chen H.
      • et al.
      Clinical characteristics of 113 deceased patients with coronavirus disease 2019, retrospective study.
      . The same study demonstrated lower thyroid stimulating hormone and free triiodothyronine concentrations in deceased patients, possibly due to critical illness-associated eythyroid sick syndrome
      • Chen T.
      • Wu Di
      • Chen H.
      • et al.
      Clinical characteristics of 113 deceased patients with coronavirus disease 2019, retrospective study.
      .
      Hyponatremia is a known sequela of lower respiratory tract infections, that is possibly induced by the inappropriate secretion of anti-diuretic hormone.
      • Dixon B.S.
      • Anderson R.J.
      Pneumonia and the syndrome of inappropriate antidiuretic hormone secretion, Don't pour water on the fire.
      • Hausman-Kedem M.
      • Reif S.
      • Danino D.
      • et al.
      Mechanism of hyponatremia in community-acquired pneumonia, does B-type natriuretic peptide play a causative role?.
      • Shepshelovich D.
      • Leibovitch C.
      • Klein A.
      • et al.
      The syndrome of inappropriate antidiuretic hormone secretion, distribution and characterization according to etiologies.
      However, not many studies currently report measurement of electrolytes, including sodium. Among these studies, none has depicted statistically or clinically significant differences of sodium or potassium concentrations between severe/fatal and less severe COVID-19 patient groups.
      • Chen T.
      • Wu Di
      • Chen H.
      • et al.
      Clinical characteristics of 113 deceased patients with coronavirus disease 2019, retrospective study.
      ,
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Guan W.-.J.
      • Ni Z.-.Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Xu X.-.W.
      • Wu X.-.X.
      • Jiang X.-.G.
      • et al.
      Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China, Retrospective case series.
      Although acid-base balance disturbances are expected among COVID-19 patients with multi-organ injury, few data are available; Zhou et al. disclosed significantly higher frequency of acidosis in non-survivors compared to survivors (30% vs 1% respectively, p<0.0001), while Chen et al. reported lower bicarbonate concentration in patients who died, without reporting the statistical significance of this finding.
      • Chen T.
      • Wu Di
      • Chen H.
      • et al.
      Clinical characteristics of 113 deceased patients with coronavirus disease 2019, retrospective study.
      ,
      • 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.
      Importantly, but not surprisingly, in the latter study more than 50% of the deceased patients had arterial partial pressure of oxygen (PaO2) of <60 mmHg (compared to 0% in the survivor group), while none in the same group had a partial pressure of oxygen to fraction of inspired oxygen ratio (PaO2:FiO2) of >3001. Hence, arterial blood gases constitute important prognostic tools for disease severity and poor outcomes, as they are directly associated with the degree of functional lung damage.

      Conclusion

      Recent clinical research among COVID-19 patients indicates that SARS-CoV-2 infection causes systemic disease, involving multiple organs and systems, including hyperactivation of the immune system, the nervous system and the clotting system. These in turn leading to pathologies in several organs, including the heart, liver and kidneys. In order to stratify patients at risk and to monitor high risk patients at intensive care units, tight laboratory diagnostics provide instrumental information. Laboratory tests can be used as prognostic markers for increased risk and mortality. The spectrum of currently available biomarkers is sufficient to fullfill this purpose. A major limitation of available studies is that the time point of sampling/biomarker assessment since onset of symptoms and/or presentation at health care facilities is not clearly mentioned. Furthermore, currently, there are no internationally acceptable criteria regarding disease severity, which renders evaluation of data quite subjective, depending on individual study investigations. Over the next months and years, with the use of further knowledge on the pathogenesis of SARS-CoV-2 infections, an even more comprehensive list of suitable biomarkers will be developed (Fig. 1 and Tables 1, 2).

      Declaration of Competing Interest

      CS and HR received consultancy fees and research funding from Hycor Biomedical and Thermo Fisher Scientific, research funding from Mead Johnson Nutrition (MJN), and consultancy fees from Bencard Allergie.

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