REVIEW

published: 27 April 2022

doi: 10.3389/fimmu.2022.857573

Laboratory Biomarkers for Diagnosis

and Prognosis in COVID-19
Denise Battaglini 1,2,3, Miquéias Lopes-Pacheco 4, Hugo C. Castro-Faria-Neto 5,
Paolo Pelosi 1,2 and Patricia R. M. Rocco 4,6,7*
1 Anesthesia and Intensive Care, San Martino Policlinico Hospital, Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS)
for Oncology and Neuroscience, Genoa, Italy, 2 Department of Surgical Science and Integrated Diagnostics (DISC), University
of Genoa, Genoa, Italy, 3 Department of Medicine, University of Barcelona, Barcelona, Spain, 4 Laboratory of Pulmonary
Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil,
5 Laboratory of Immunopharmacology, Oswaldo Cruz Institute - Fiocruz, Rio de Janeiro, Brazil, 6 COVID-19 Virus Network

from Brazilian Council for Scientific and Technological Development, Brası´lia, Brazil, 7 COVID-19 Virus Network from
Foundation Carlos Chagas Filho Research Support of the State of Rio de Janeiro, Rio de Janeiro, Brazil

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) causes a wide spectrum

of clinical manifestations, with progression to multiorgan failure in the most severe cases.
Several biomarkers can be altered in coronavirus disease 2019 (COVID-19), and they can
be associated with diagnosis, prognosis, and outcomes. The most used biomarkers in
Edited by: COVID-19 include several proinflammatory cytokines, neuron-specific enolase (NSE),
Xin-Xin Zhang, lactate dehydrogenase (LDH), aspartate transaminase (AST), neutrophil count,
Shanghai Public Health Clinical Center,
China neutrophils-to-lymphocytes ratio, troponins, creatine kinase (MB), myoglobin, D-dimer,
Reviewed by: brain natriuretic peptide (BNP), and its N-terminal pro-hormone (NT-proBNP). Some of
Barbara Bottazzi, these biomarkers can be readily used to predict disease severity, hospitalization, intensive
University of Milan, Italy
Chun Fang Gao,
care unit (ICU) admission, and mortality, while others, such as metabolomic and
Shanghai University of Traditional proteomic analysis, have not yet translated to clinical practice. This narrative review
Chinese Medicine, China aims to identify laboratory biomarkers that have shown significant diagnostic and
*Correspondence: prognostic value for risk stratification in COVID-19 and discuss the possible clinical
Patricia R. M. Rocco
[email protected] application of novel analytic strategies, like metabolomics and proteomics. Future
research should focus on identifying a limited but essential number of laboratory
Specialty section: biomarkers to easily predict prognosis and outcome in severe COVID-19.
This article was submitted to
Viral Immunology, Keywords: biomarkers, COVID-19, inflammation, metabolomics, proteomics
a section of the journal
Frontiers in Immunology

Received: 18 January 2022 Abbreviations: ACE2, angiotensin receptor 2; ARDS, acute respiratory distress syndrome; AST, aspartate transaminase; BNP,
Accepted: 31 March 2022 brain natriuretic peptide; cAMP, cyclic adenosine monophosphate; CD, cluster differentiation; CK, creatine kinase; COVID-
Published: 27 April 2022 19, coronavirus disease 2019; CRP, C-reactive protein; CT, computed tomography; ECG, electrocardiography; ESR,
erythrocyte sedimentation rate; GFAP, glial fibrillary acidic protein; HDL, high-density lipoprotein; ICU, intensive care
Citation:
unit; IL, interleukin; KIM, kidney injury molecule; L-FABP, liver-type fatty acid binding protein; LDH, lactate dehydrogenase;
Battaglini D, Lopes-Pacheco M, LDL, low-density lipoprotein; MR-proADM, mid-regional pro-adrenomedullin; MRI, magnetic resonance imaging; NfL,
Castro-Faria-Neto HC, Pelosi P and neurofilament light polypeptide; NGAL, neutrophil gelatinase-associated lipocalin; NK, natural killer; NP, natriuretic peptides;
Rocco PRM (2022) Laboratory NSE, neuron-specific enolase; NT-proBNP, N-terminal pro-hormone BNP; PPAR, peroxisome proliferator-activated receptor;
Biomarkers for Diagnosis and RASS, renin-angiotensin- aldosterone system; SARS-CoV-2, severe acute respiratory syndrome-coronavirus-2; ssRNA, single-
Prognosis in COVID-19. stranded ribonucleic acid; sTNFRI, soluble TNF receptor I; sVCAM, soluble vascular cell adhesion molecule; TMPRSS2,
Front. Immunol. 13:857573. transmembrane serine protease 2; TNF, tumor necrosis factor; TREM, triggering receptor expressed on myeloid cell; TRP,
doi: 10.3389/fimmu.2022.857573 tryptophan metabolic pathway; TTE, transthoracic electrocardiography; vWF, von Willebrand Factor.

Frontiers in Immunology | www.frontiersin.org 1 April 2022 | Volume 13 | Article 857573

Battaglini et al. Biomarkers for Prognosis in COVID-19

INTRODUCTION while the M protein is involved in viral assembly and delineates

the shape of the viral envelope; finally, the N protein binds directly
Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) to viral RNA (11). The pathogenic mechanisms of SARS-CoV-2
causes a wide spectrum of clinical manifestations, from mild include 1) direct epithelial damage, 2) dysregulated immune
respiratory symptoms to pneumonia and, in more severe cases, response, 3) ACE2 dysregulation and downregulation of the
multiple organ failure (1). The mechanisms underlying renin-angiotensin- aldosterone system (RAAS), 4) direct
multisystem involvement may include an unbalanced immune endothelial damage, and, possibly, 5) tissue fibrosis (11). Hence,
response that facilitates the progression of coronavirus disease- patients with severe COVID-19 are at high risk of multiple organ
2019 (COVID-19). This hypothesis has been confirmed by involvement and, ultimately, death. Indeed, the virus has been
laboratory biomarker alterations, showing greater potential for identified in multiple tissues, including endothelial, liver, kidney,
abnormal immune response, mainly an increase in neutrophil pulmonary, and neuronal cells, suggesting direct invasion as
counts and a substantial reduction in lymphocyte counts, thus possible pathological mechanism underlying systemic effects (1).
altering the neutrophil-to-lymphocyte ratio. Such an abnormal Therefore, laboratory biomarkers of organ damage play a key role
immune response is driven by an increased serum concentration in the diagnosis, prediction, and prognosis of patients at high risk
of many pro-inflammatory mediators. These include interleukin of multiorgan involvement, and their use should be implemented
(IL)-1b, IL-2, IL-6, IL-8, interferon (IFN)-g-induced protein 10, in clinical practice (1). Table 1 summarizes the most investigated
granulocyte colony-stimulating factor, monocyte chemoattractant biomarkers in COVID-19, while Figure 1 depicts possible
protein 1, macrophage inflammatory protein-1a, and tumor multiorgan involvement in COVID-19. In the following section,
necrosis factor-a, among others (2–5). Nevertheless, the we will describe individual organ systems and how they can be
inflammatory cytokine storm in patients with COVID-19 is less affected by severe COVID-19, associated laboratory and clinical
injurious than that observed in patients with sepsis or acute biomarkers of damage, severity, and outcome, and their potential
respiratory distress syndrome (ARDS) but without COVID-19 utility for patient management.
(6), thus raising questions regarding the mechanisms underlying
multiorgan involvement in COVID-19.
Several biomarkers other than cytokines have been found
altered in COVID-19, and are associated with diagnosis,
DIAGNOSTIC AND PROGNOSTIC VALUE
prognosis and outcomes (7). Some of these biomarkers can be OF BIOMARKERS
easily used to predict disease severity, hospitalization, intensive
Biomarkers reflecting multiple organ involvement and/or
care unit (ICU) admission, and mortality, while others, like
pharmacological effects have been widely examined in critically
metabolomic and proteomic analysis, are still of purely
ill patients. Some of these biomarkers are also used to monitor
investigational concern and difficult to translate into clinical
dysfunction in distinct organs at the same time, due to their
practice, despite their prognostic potential (8–10).
redundancy or non-specificity. However, the most appropriate
The aim of this narrative review is to identify laboratory
biomarkers to be studied in critically ill patients with COVID-19
biomarkers that have shown significant diagnostic and
have yet to be defined. Figure 2 depicts a proposed algorithm for
prognostic value for risk stratification in COVID-19 and to
critical care management which includes the investigation of
discuss the possible clinical application of novel analytic
biomarkers in severe COVID-19 patients at ICU admission.
strategies, such as metabolomics and proteomics.
Respiratory System
The lungs are usually the organs affected primarily by SARS-CoV-
POTENTIAL FOR MULTIORGAN 2, due to their large and highly vascularized surface area (11). The
INVOLVEMENT IN COVID-19 pathogenesis of COVID-19 in the lung includes an initial phase of
local inflammation, endothelial cell damage, and antifibrinolytic
SARS-CoV-2 is an enveloped, single-stranded ribonucleic acid activation in the upper and lower respiratory tracts, followed by
(ssRNA) virus. The SARS-CoV-2 genome is composed of two repair mechanisms that can elicit the restoration of normal
polypeptides encoded between two open-reading frames that are pulmonary architecture. Inflammation is followed by platelet
processed by viral proteases to produce nonstructural proteins recruitment with degranulation, clot formation, altered vessel
(11). These proteins are involved in viral replication and permeability, and accumulation of leukocytes in the injury site,
suppression of host innate immune defense. On the other hand, leading to the recruitment of other inflammatory cells with the
structural proteins of SARS-CoV-2 include the spike (S), envelope involvement of specific cytokines (i.e., IL-4, IL-13, transforming
(E), and nucleocapsid (N) protein, as well as the membrane (M) growth factor-b) that are also responsible for pro-fibrotic
glycoprotein. The S protein is a transmembrane glycoprotein that activity (12).
is located on the viral surface and cleaved by host-cell proteases. SARS-CoV-2 lung infection causes a wide variety of clinical
After anchoring the S protein, SARS-CoV-2 enters host cells via manifestations and symptoms, from asymptomatic, mild, and
angiotensin receptor-2 (ACE2), thus activating transmembrane moderate disease to severe COVID-19. Severe and critical illness
serine protease 2 (TMPRSS2), cathepsin B and L. The E protein is accounts for up to 14% and 5% of cases, respectively, with the
a glycoprotein involved in virion maturation and pathogenesis, ARDS occurring in 10-20% of patients; multiorgan failure and

Frontiers in Immunology | www.frontiersin.org 2 April 2022 | Volume 13 | Article 857573

Battaglini et al. Biomarkers for Prognosis in COVID-19

TABLE 1 | Laboratory biomarkers in COVID-19.

Biomarkers Clinical significance

Pulmonary function NSE Dyspnea

LDH, AST Mortality at admission, longer IMV
Surfactant protein-D, angiopoietin-2, TREM-1, TREM-2 Severity
Thiol, ferritin, LDH ARDS development
Platelet count, neutrophils/lymphocyte ratio, CRP, D-dimer, ferritin Survival at extubation
Kynurenine, p-cresol sulphate Longer IMV
Metabolomic/proteomic: PPAR, D-arginine, D-ornithine, TRP, alpha linoleic Fibrosis
Inflammation and infection PCT Severity, mortality
Neutrophil count Clinical outcome, mortality
Neutrophil/lymphocyte ratio Severity, mortality
Lymphocyte count, CD3+, 4+, 8+, 25+, 127-, NK cells Severity, mortality
Cardiovascular function NPs, troponins CV disease, inflammation, mortality
MR-proADM Survival
CK-MB, myoglobin, D-dimer, BNP, NT-proBNP, neutrophil/lymphocyte ratio Prognosis
Coagulation and hemostasis D-dimer Mortality
Plasma fibrinogen Hyperinflammation, severity
sVCAM-1, vWF, thrombomodulin, sTNFRI, HS, C5b9, PAI-1, alpha-2 antiplasmin Severity
vWF, ADAMTS13 Mortality
Endothelial dysfunction Severity of pulmonary impairment
Metabolic system HDL cholesterol Risk of hospitalization
LDL cholesterol Inflammation
Vitamin A ARDS development, mortality
Metabolomic/proteomic: cAMP Mortality
Thyroid hormones Severity, mortality
Neurological manifestations GFAP, NfL, tau, S100B, NSE, inflammatory markers Inflammation, severity
D-dimer, LDH, ESR, CRP, lymphocytes, PCT, creatinine Occurrence of ischemic stroke
Kidney and liver function Urine 11-dehydro-thromboxane B2, 8-hydroxy-2’-deoxyguanosine, L-FABP Hospitalization
N-acetyl-b-D-glucosaminidase, b2-microglobulin, a1-microglobulin, L-FABP Hyperinflammation
PCT, arterial saturation of oxygen, blood urea nitrogen Acute kidney injury
Creatinine Acute kidney injury, mortality
Urine blood, urine weight Mortality
Albumin, direct albumin, neutrophils, lymphocytes, mean corpuscular hemoglobin Severity

ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs, ARDS, acute respiratory distress syndrome, AST, aspartate aminotransferase, BNP, brain natriuretic peptide,
cAMP, adenosine cyclic monophosphate, CD, cluster differentiation, CK-MB, creatine kinase, CRP, C-reactive protein, CV, cardiovascular, ESR, erythrocyte sedimentation rate, GFAP,
glial fibrillary acidic protein, HDL, high density lipoproteins, HS, heparan sulfate, IMV, invasive mechanical ventilation, L-FABP, liver-type fatty acid binding protein, LDH, lactate
dehydrogenase, LDL, low density lipoproteins, MR-proADM, mid-regional pro-adrenomedullin, NfL, neurofilament light polypeptide, NK, natural killer, NPs, natriuretic peptides, NSE,
neuron specific enolase, NT-proBNP, N-terminal pro-hormone, PAI, plasminogen activator inhibitor, PCT, procalcitonin, PPAR, peroxisome proliferator-activated receptors, sTNFRI
soluble tumor necrosis factor receptor I, sVCAM-1, vascular cells adhesion molecule-1, TREM, triggering receptor expressed on myeloid cells, TRP, transient receptor potential channel,
vWF, von Willebrand.

death may supervene (13, 14). Various phenotypes have been (AST) have all been associated with lower risk of mortality in
identified by computed tomography (CT) (15, 16), including COVID-19 patients who ultimately required intubation and
phenotype L or 1, which is characterized by low compliance, mechanical ventilation (22). Surfactant protein-D, angiopoietin-
altered ventilation and perfusion, and shunting with focal hypo/ 2, triggering receptor expressed on myeloid cell (TREM)-1, and
hyper-perfused ground-glass opacities; and phenotype H or 2, TREM-2 levels were found to be higher in mild/moderate and
which is identified by an inhomogeneous distribution of atelectasis severe/critical COVID-19 pneumonia than in asymptomatic and
with a patchy ARDS-like pattern (17, 18). Progressive evolution of uncomplicated cases. Moreover, these biomarkers correlated well
COVID-19 (19) may lead to phenotype F, caused by mechanical with clinical severity (23, 24). In severe COVID-19 cases, total
stretch of lung epithelial cells and pathological fibro-proliferation thiol, ferritin, and LDH were identified as prognostic biomarkers
and remodeling of the extracellular matrix, with increased for ARDS development (25). At extubation, COVID-19 survivors
expression of pro-fibrotic markers, as is mainly typical of severe had higher platelet counts and neutrophil-to-lymphocyte ratios
forms of lung disease (20). and lower C-reactive protein (CRP), D-dimer, ferritin, LDH, and
Although not specific to pulmonary disease, several biomarkers AST (22).
of different stages of lung involvement in COVID-19 have been
identified and have been associated with pulmonary and systemic Infection and Systemic
hyperinflammation and fibrotic damage (12). In the early disease Inflammatory Response
course, neuron-specific enolase (NSE) can be used to differentiate Following SARS-CoV-2 invasion of the host cells, the virus
patients who are going to develop dyspnea (21). On admission, replicates at the infection site, thus triggering activation of the
higher lymphocyte and platelet counts and lower ferritin, D- innate and adaptive immune responses (26). Neutrophils are
dimer, lactate dehydrogenase (LDH), and aspartate transaminase rapidly recruited to infection foci, while innate cells recognize

Frontiers in Immunology | www.frontiersin.org 3 April 2022 | Volume 13 | Article 857573

Battaglini et al. Biomarkers for Prognosis in COVID-19

FIGURE 1 | COVID-19 multiple organ dysfunction. This figure shows the potential for multiorgan involvement in COVID-19. Respiratory (AIP, acute interstitial
pneumonia; ARDS, acute respiratory distress syndrome; DAD, diffuse alveolar damage), renal, cardiovascular, coagulative/hemostatic, liver, gastrointestinal,
metabolic/endocrine, and cerebral functions and systems, as well as their possible alterations, are presented.

the virus and secrete multiple cytokines. Antigen-presenting cells patients more than 75 years old (34). Neutrophil count was also
recognize viral antigens which are carried to the local lymph predictive of clinical outcome in hospitalized COVID-19 patients
nodes, while activating the T-helper cell response, which is also (35), while the neutrophil-to-lymphocyte ratio was strongly
responsible for stimulating B cells to secrete antibodies (27). The associated with severity and mortality in COVID-19 (36).
systemic immune-inflammatory response is activated; if left Additionally, total lymphocyte count, cluster differentiation (CD)
unchecked, this may progress to multiorgan illness (28). 3+, CD4+, CD8+, CD25+, CD127– T cells, and natural killer (NK)
Patients with severe COVID-19 are highly susceptible to cells were found to be depressed in severe COVID-19 (37), whereas
superimposed bacterial, fungal, and viral infections, including C-reactive protein, erythrocyte sedimentation rate, and IL-6 –
ventilator-associated pneumonia and bloodstream infection, common markers of inflammation – were elevated (38).
among others (29, 30). As for systemic biomarkers of infection,
procalcitonin is a predictor of disease severity (31), and can be useful Cardiovascular System
to guide antimicrobial stewardship (32, 33). Another study found an SARS-CoV-2 can directly trigger endothelial dysfunction, causing
association between procalcitonin and mortality in COVID-19 a status known as COVID-19-associated coagulopathy. After viral

Frontiers in Immunology | www.frontiersin.org 4 April 2022 | Volume 13 | Article 857573

Battaglini et al. Biomarkers for Prognosis in COVID-19

FIGURE 2 | Proposed algorithm for the management of patients with COVID-19 at ICU admission. This figure shows a potential algorithm for initial patient
management at ICU admission, including the most useful biomarkers to be used in the COVID-19 critical care setting. Neurological system: sequential transcranial
doppler (TCD) and/or optic nerve sheath diameter (ONSD) in sedated patients for whom conventional neurological evaluation is impossible. Cardiovascular system:
electrocardiogram and echocardiography, as well as continuous monitoring of mean arterial pressure (MAP) and heart rate (HR), are suggested on ICU admission.
Respiratory system: computed tomography (CT) scan is the gold standard; if not feasible, chest X-ray, CT angiography, and/or lung ultrasound should be performed.
Lactate dehydrogenase (LDH), C-reactive protein (CRP), neuron specific enolase (NSE), neurofilament light polypeptide (NfL), glial fibrillary acidic protein (GFAP),
thyrotropic stimulating hormone (TSH), NGAL, aspartate transaminase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (gGT), interleukin-6 (IL-6).
BNP, brain natriuretic peptide; UN, urea nitrogen; NT-proBNP, N-terminal pro-hormone.

entry into the cells, increased vascular permeability and tissue cardiomyopathy, acute kidney injury, and, as noted above,
factor expression in subendothelial cells, with activation of systemic inflammatory response with the release of several
platelets and leukocytes, may trigger the coagulation cascade. cytokines and chemokines (45). Triggering mechanisms may be
Endothelial damage and a generalized inflammatory state are attributed to an imbalance between heightened cardiac workload
drivers of thrombosis, which can contribute to cardiovascular and reduced oxygen supply secondary to systemic conditions, with
manifestations (39). possible type-2 myocardial infarction (46).
Cardiovascular manifestations of COVID-19 are frequently Cardiac biomarkers (47), electrocardiography (ECG), and
reported (2, 40). Acute heart failure and exacerbation of chronic transthoracic echocardiography (TTE) play a pivotal role in risk
heart failure are reported in up to 20-30% of hospitalized patients, stratification and early detection of cardiovascular complications,
and carry high mortality rates, especially in patients with severe as well as to guide treatment (48, 49). Recent evidence confirmed
comorbidities (41–43). Acute coronary syndrome has been that cardiac biomarkers, including natriuretic peptides (NPs) and
reported in a high proportion of patients, probably because of troponins, may reflect cardiovascular involvement and
plaque rupture, coronary spasm, or microthrombi triggered by inflammation in COVID-19, and are strongly associated with
systemic inflammation and cytokine storm (44). In general, the poor prognosis and mortality (41, 50–53). In some cases,
mechanisms underlying cardiovascular manifestations include troponin elevation in COVID-19 has been associated with ECG
increased cardiac workload, hypoxemia, hypervolemia, changes (54), ICU admission, and in-hospital death (55, 56).
myocardial injury, arrhythmias, myocarditis, stress-induced However, despite the confirmed prognostic impact of troponins,

Frontiers in Immunology | www.frontiersin.org 5 April 2022 | Volume 13 | Article 857573

Battaglini et al. Biomarkers for Prognosis in COVID-19

routine testing is still a matter of debate, because of several other response (74). Investigating lipid metabolism and its biomarkers
variables that have been associated with outcome and prognosis could thus be of diagnostic and prognostic value in COVID-19.
(48). Additionally, pre-existing cardiac disease and/or acute stress Metabolic comorbidities including obesity, diabetes,
injury may justify mild elevations in cardiac troponins, while cardiovascular, and hypertension have been associated with poor
myocarditis, Takotsubo syndrome, type 2 myocardial infarction prognosis in COVID-19 (75). A certain degree of metabolic
triggered by severe respiratory failure, systemic hypoxemia, or dysregulation has been found in COVID-19, possibly due to
shock are mostly associated with more marked increase in immune-triggered inflammation and hypercoagulability, as well
troponins (44, 57, 58). Other cardiac and non-cardiac as microbial changes in host physiology (10, 76). Indeed, COVID-
biomarkers are common findings in COVID-19-associated 19 patients with lower levels of high-density lipoprotein (HDL)
cardiovascular disease, including creatine kinase (CK)-MB, cholesterol are more susceptible to hospitalization, while low-
myoglobin, D-dimer, brain natriuretic peptide (BNP) and its N- density lipoprotein (LDL) cholesterol was associated with higher
terminal pro-hormone (NT-proBNP), and neutrophil-to- inflammation (77). Critically ill patients with COVID-19 showed
lymphocyte ratio (55, 59–61). Myoglobin seems to offer higher significantly lower levels of vitamin A than non-critical ones, and
prognostic accuracy than other cardiac-specific biomarkers this was associated with higher inflammation (78). Vitamin A
(troponins and CK-MB) in COVID-19 (62). Moreover, mid- levels below 0.2 mg/L were significantly associated with the
regional pro-adrenomedullin (MR-proADM) levels were found developments of ARDS and higher mortality (78). Vitamin D, a
to be associated with endothelial dysfunction and mortality in well-known regulator of phosphate and calcium metabolism with
COVID-19, potentially making it an optimal biomarker for the immunomodulatory functions, seems to not influence mortality or
prediction of survival in this patient population (63). Nevertheless, hospital length of stay in COVID-19 (79, 80). Finally, thyroid
only limited evidence exists so far to define any of these hormones showed marked association with disease severity and
biomarkers as an independent predictor of prognosis in mortality, suggesting the importance of early assessment of
COVID-19 (48, 64). thyroid function – and, when necessary, initiation of treatment
– in hospitalized COVID-19 patients (81).
Coagulation and Hemostasis
Coagulation derangement is a well-known systemic effect of Neurologic Involvement
COVID-19 that can originate from direct or indirect viral Pathogenetic mechanisms of SARS-CoV-2 neurologic
impact on the endothelium, or from immunothrombosis (65). manifestations include possible spreading of the virus across the
COVID-19 can cause alterations in the coagulation cascade, with blood-brain barrier via leukocyte migration or sluggish movement
imbalance of the regulatory mechanisms of coagulation and of blood within the microcirculation, thus binding to endothelial
fibrinolysis, altered platelet function, and a hyperinflammatory cells. Cells which may present ACE2 receptors, including neurons,
response (11, 65). In this context, D-dimer has been identified astrocytes, and oligodendrocytes, can all be affected directly by
among the first altered coagulation biomarkers in COVID-19, and viral entry and activate the local immune response. As a
is predictive of mortality on admission (66). Similarly, plasma consequence of neuronal involvement, several biomarkers of
fibrinogen appears to be associated with hyperinflammation and neuroinflammation and damage can be detected (82).
disease severity in COVID-19 (67). A coagulopathy signature Although COVID-19 rarely affects the brain as a primary
diagnostic of COVID-19 has been identified, including elevated manifestation, neurological complications are common in this
levels of soluble vascular cell adhesion molecule (sVCAM)-1 (68), patient population (82–84). Patients with neurological
von Willebrand Factor (vWF), thrombomodulin, soluble tumor complications, compared to those without, may experience longer
necrosis factor (TNF) receptor I (sTNFRI), heparan sulfate, C5b9 hospital stays, and the duration of mechanical ventilation can be
complement, plasminogen activator inhibitor (PAI)-1, and alpha- associated with the risk of developing new neurological complications
2 antiplasmin, among others. Some of these markers, such as (84, 85). CT and magnetic resonance imaging (MRI) are considered
sVCAM-1, vWF, sTNFRI, and heparan sulfate, were also the gold standard for detecting cerebral derangements, although the
associated with disease severity (69). Fibrinogen, thrombin peak, use of methods which involve exposure to ionizing radiation in non-
vWF, and ADAMTS13 at admission and elevated vWF : Ag to primarily brain-injured patients can only be justified in case of high
ADAMTS13 activity ratio were associated with severity and higher suspicion of neurological complications (86). The use of multimodal
risk of death (70, 71). Endothelial dysfunction seems to be neuromonitoring has received increasing attention as a means of
persistent after resolution of COVID-19, and directly associated identifying patients at higher risk of brain derangement because of its
with the severity of pulmonary impairment (72). low cost, speed, safety, and ready availability. However, the use of
neuromonitoring tools is still mainly limited to specific settings (i.e.,
Metabolic Function ICU) and patient populations (i.e., those with primary brain
Sphingolipid metabolism regulates the inflammation and immune injury) (84).
response through the conversion of sphingosine to sphingosine 1- Other than imaging, blood biomarkers can detect brain damage
phosphate, increasing the release of lymphocytes into the blood, and predict prognosis efficiently. Blood biomarkers for the study of
with subsequent systemic inflammation and release of cytokines brain derangements include glial fibrillary acidic protein (GFAP),
and chemokines in COVID-19 (73). Like lipid metabolism, fat- neurofilament light polypeptide (NfL), tau, S100B calcium binding
soluble vitamins such as vitamin D have been implicated in protein, NSE, and inflammatory markers. Increased GFAP staining
suppressing the cytokine storm and enhancing the immune has been found in postmortem analysis of brain tissue from patients

Frontiers in Immunology | www.frontiersin.org 6 April 2022 | Volume 13 | Article 857573

Battaglini et al. Biomarkers for Prognosis in COVID-19

with COVID-19 (87), and NfL was significantly associated with microglobulin, a1-microglobulin, and L-FABP, which are all
COVID-19 status (88). Another study reported that GFAP was markers of tubular injury, were significantly associated with
increased in both moderate and severe COVID-19 cases, whereas inflammation, as were IL-6 levels (102). Indeed, another
serum NfL was increased only in severe cases compared to controls observational study confirmed the association between pro-
(89). However, another study reported that serum NfL, although inflammatory cytokines, urinary cytokines, and urinary kidney
elevated across patients hospitalized with COVID-19, was not injury markers (103). Procalcitonin was associated with acute
associated with neurological manifestations. Additionally, the kidney injury in COVID-19, and a score including simple and
usual close correlation between cerebrospinal fluid and serum easily accessible variables such as procalcitonin, arterial saturation
NfL was not found, suggesting serum NfL elevation in the non- of oxygen, and blood urea nitrogen was shown to be predictive of
neurological patients may reflect peripheral nerve damage in acute kidney injury (104).
response to severe illness (90). In COVID-19 patients with altered Altered serum creatinine levels with decreased kidney function
NfL and GFAP, values of these markers had normalized in all at admission and up to 24 hours thereafter were significantly
individuals at 6-month follow-up, suggesting that post-COVID-19 associated with acute kidney injury and in-hospital mortality
neurological sequelae may be not accompanied by ongoing brain (105). Additionally, urine blood >0.03 mg/dL and urine specific
injury (91). Inflammatory and coagulatory markers like D-dimer, gravity >1.026 were associated with acute kidney injury, ICU
LDH, erythrocyte sedimentation rate (ESR), and CRP were admission, and higher mortality (106).
independently associated with the occurrence of ischemic stroke Abnormal liver and hepatobiliary function have been also
in COVID-19 (92, 93), while higher age, diabetes mellitus, and identified in COVID-19 (107). A systematic review and meta-
hypertension were found not to be significant predictors of stroke in analysis showed a cumulative prevalence of liver disease of 24% in
this population, despite being known predictors of non-COVID-19 COVID-19, with possible alterations in albuminemia, liver enzymes,
stroke (93). Levels of lymphocytes, procalcitonin, and creatinine and total bilirubin (108). Recent findings showed that some liver and
were higher in COVID-19 stroke patients (94). S100B was higher in renal biomarkers, including albumin, direct bilirubin, neutrophil and
patients with mild and severe COVID-19 than in healthy controls, lymphocyte counts, and mean corpuscular hemoglobin, are
and may be a marker of disease severity (95). Antiphospholipid associated with risk of developing severe COVID-19 (107).
antibodies (i.e., anti-phosphatidylserine/prothrombin) were higher Moreover, the presence of pre-existing liver fibrosis with silent liver
in COVID-19 patients, particularly those with neurological injury significantly influenced mortality in COVID-19 (109).
manifestations, than in controls. In contrast, anticardiolipin
antibodies were not associated with neurologic involvement in
COVID-19 (96).
FUTURE PERSPECTIVES: METABOLOMIC
Kidney and Liver AND PROTEOMIC BIOMARKERS AND
COVID-19 may cause kidney and liver injury by either direct MACHINE LEARNING MODELS
infection of cells, via host immune clearance and immune
tolerance disorders, endothelium-associated vasculitis, thrombus Given the significant immune dysregulation of COVID-19 patients,
formation, metabolism and glucose disorder, or tissue hypoxia. As the interplay between metabolism and immunity may play a pivotal
a consequence, biomarkers of endothelial, renal, hepatic, vascular, role in the disease course (110). Additionally, oxygen deprivation
or hypoxic damage can help in the detection of new organ may affect homeostasis in tissues and organs such as the lung, brain,
involvement and assist in determining prognosis (97). kidney, and liver. The modulation of oxygen homeostasis and
As part of multiorgan involvement in COVID-19, kidney response to hypoxia is mainly mediated by glycolysis and the
function might be altered directly by viral invasion or may occur lactate cycle. This has increased research interest in proteomic
secondary to multiple organ failure due to systemic inflammation or and metabolomic methods to investigate pathways linked to energy
aggressive therapies (98). Around 25% of patients hospitalized with production and amino acid metabolism in patients with SARS-
COVID-19 were reported to develop acute kidney injury, including CoV-2 infections (110). Metabolomic analyses in COVID-19
low molecular weight proteinuria, Fanconi syndrome, and tubular patients with and without pulmonary fibrosis revealed that
injury (98). Moreover, regional inflammation, endothelial injury, pathways including the peroxisome proliferator-activated
and microthrombi have been identified as major causative factors of receptor (PPAR), D-arginine and D-ornithine metabolism,
renal pathology in COVID-19. This is also sustained by the fact that inflammatory tryptophan metabolic pathway (TRP), and alpha-
anti-inflammatory drugs, such as steroids, play a key role in limiting linolenic acid metabolism were significantly increased in fibrotic
renal disease progression (98). Classic diagnostic biomarkers of lungs, thus suggesting that PPAR signaling is one of the main
kidney damage include creatinine, neutrophil gelatinase-associated pathways involved in the formation and development of lung
lipocalin (NGAL), cystatin C, kidney injury molecule-1 (KIM-1), fibrosis in COVID-19 (9). A proteomic and metabolomic analysis
blood and urinary urea nitrogen, and urinary proteins (99, 100). identified hypoxanthine and betaine as predictors of ICU stay, and
Novel urinary biomarkers have been proposed in COVID-19, early ICU admission, elevated creatinine, and D-dimer were found
including urine 11-dehydro-thromboxane B2, 8-hydroxy-2′- to be associated with these pathways (8). Longer duration of
deoxyguanosine, and liver-type fatty acid binding protein (L- invasive mechanical ventilation was associated with the
FABP) levels, all of which were higher in this patient cohort at the kynurenine and p-cresol sulfate pathways (8). Several markers of
time of hospitalization (101). N-acetyl-b-D-glucosaminidase, b2- metabolic function identified via metabolomic analysis were

Frontiers in Immunology | www.frontiersin.org 7 April 2022 | Volume 13 | Article 857573

Battaglini et al. Biomarkers for Prognosis in COVID-19

associated with in-hospital mortality, including cyclic adenosine Furthermore, novel analytic strategies including metabolomics
monophosphate (cAMP), which plays a role in SARS-CoV2 and proteomics offer interesting insights for early detection of
endocytosis in the initial phase of the disease (10). Another major patients at higher risk of severe disease and death. However, their
signature of the serum metabolome in COVID-19 was lactic acid, as limited availability restricts their widespread clinical use. Further
well as spermidine and spermine. Many other metabolites were investigations are warranted to identify a core set of laboratory
commonly increased, including glutamate, aspartate, biomarkers which can be used in daily clinical practice to easily
phenylalanine, b-alanine, ornithine, arachidonic acid, choline, predict prognosis and outcome in hospitalized patients with
and xanthine (110). Recent machine learning models have been severe COVID-19.
developed to support decision making and risk stratification in
COVID-19. Most predictive models rely on demographic and
clinical variables. However, biomarkers have recently shown good
correlation with severity of disease and mortality in COVID-19 AUTHOR CONTRIBUTIONS
modeling (111). One example was a large study of 2,895 consecutive
patients with COVID-19 in whom three biomarkers measured at DB and ML-P: review, design, writing, editing. HC-F-N and PP:
admission were found to reflect pathobiological axes of myocardial editing. PR: review, design, editing, senior contribution. All authors
injury, altered coagulation, and inflammation. The machine contributed to the article and approved the submitted version.
learning model concluded that patients with low levels of these
biomarkers were at lower risk of critical disease and in-hospital
mortality (112). In conclusion, the alterations found in the serum
metabolome of patients with COVID-19 may reflect a more FUNDING
complex systemic derangement affecting carbon and nitrogen This work was supported by the Brazilian Council for Scientific
liver metabolism, but further research is needed to completely and Technological Development (COVID-19-CNPq; 401700/
understand the impact of these alterations on routine clinical 2020-8 and 403485/2020-7); Rio de Janeiro State Research
practice. Machine learning models can be promising in risk Foundation (COVID-19-FAPERJ; E-26/210.181/2020); and
stratification in COVID-19. However, further investigations are Funding Authority for Studies and Projects (01200008.00), Brazil.
needed to develop mathematical models that can help clinicians
select the right parameters and interpret results.

ACKNOWLEDGMENTS
CONCLUSIONS
The authors express their gratitude to Mrs. Moira Elizabeth
Laboratory biomarkers have shown significant diagnostic and Schottler and Mr Filippe Vasconcellos for their assistance in
prognostic value for risk stratification in COVID-19. editing the paper.

7. Andrianto, Al-Farabi MJ, Nugraha RA, Marsudi BA, Azmi Y. Biomarkers of

REFERENCES Endothelial Dysfunction and Outcomes in Coronavirus Disease 2019
1. Robba C, Battaglini D, Pelosi P, Rocco PRM. Multiple Organ Dysfunction in (COVID-19) Patients: A Systematic Review and Meta-Analysis. Microvasc
SARS-CoV-2: MODS-CoV-2. Expert Rev Respir Med (2020) 14:865–8. Res (2021) 138:104224. doi: 10.1016/j.mvr.2021.104224
doi: 10.1080/17476348.2020.1778470 8. Taleb S, Yassine HM, Benslimane FM, Smatti MK, Schuchardt S, Albagha O,
2. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical Features of et al. Predictive Biomarkers of Intensive Care Unit and Mechanical
Patients Infected With 2019 Novel Coronavirus in Wuhan, China. Lancet Ventilation Duration in Critically-Ill Coronavirus Disease 2019 Patients.
(2020) 395:497–506. doi: 10.1016/S0140-6736(20)30183-5 Front Med (2021) 8:733657. doi: 10.3389/fmed.2021.733657
3. Zhang C, Wu Z, Li J-W, Zhao H, Wang G-Q. Cytokine Release Syndrome in 9. Yang J, Chen C, Chen W, Huang L, Fu Z, Ye K, et al. Proteomics and
Severe COVID-19: Interleukin-6 Receptor Antagonist Tocilizumab May Be Metabonomics Analyses of Covid-19 Complications in Patients With
the Key to Reduce Mortality. Int J Antimicrob Agents (2020) 55:105954. Pulmonary Fibrosis. Sci Rep (2021) 11:14601. doi: 10.1038/s41598-021-
doi: 10.1016/j.ijantimicag.2020.105954 94256-8
4. Liu J, Li S, Liu J, Liang B, Wang X, Wang H, et al. Longitudinal 10. Saccon E, Bandera A, Sciumè M, Mikaeloff F, Lashari AA, Aliberti S, et al.
Characteristics of Lymphocyte Responses and Cytokine Profiles in the Distinct Metabolic Profile Associated With a Fatal Outcome in COVID-19
Peripheral Blood of SARS-CoV-2 Infected Patients. EBioMedicine (2020) Patients During the Early Epidemic in Italy. Microbiol Spectr (2021) 9:
55:102763. doi: 10.1016/j.ebiom.2020.102763 e00549–21. doi: 10.1128/Spectrum.00549-21
5. Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, 11. Lopes-Pacheco M, Silva PL, Cruz FF, Battaglini D, Robba C, Pelosi P, et al.
et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Pathogenesis of Multiple Organ Injury in COVID-19 and Potential
Covid-19. N Engl J Med (2020) 383:120–8. doi: 10.1056/NEJMoa2015432 Therapeutic Strategies. Front Physiol (2021) 12:593223. doi: 10.3389/
6. Leisman DE, Ronner L, Pinotti R, Taylor MD, Sinha P, Calfee CS, et al. fphys.2021.593223
Cytokine Elevation in Severe and Critical COVID-19: A Rapid Systematic 12. Vianello A, Guarnieri G, Braccioni F, Lococo S, Molena B, Cecchetto A, et al.
Review, Meta-Analysis, and Comparison With Other Inflammatory The Pathogenesis, Epidemiology and Biomarkers of Susceptibility of
Syndromes. Lancet Respir Med (2020) 8:1233–44. doi: 10.1016/S2213-2600 Pulmonary Fibrosis in COVID-19 Survivors. Clin Chem Lab Med (2022)
(20)30404-5 60:307–16. doi: 10.1515/cclm-2021-1021

Frontiers in Immunology | www.frontiersin.org 8 April 2022 | Volume 13 | Article 857573

Battaglini et al. Biomarkers for Prognosis in COVID-19

13. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and 32. Waris A, Din M, Iqbal N, Yar L, Khalid A, Nawaz M, et al. Evaluation of
Clinical Characteristics of 99 Cases of 2019 Novel Coronavirus Pneumonia Serum Procalcitonin Level as a Biomarker for Disease Severity in COVID-19
in Wuhan, China: A Descriptive Study. Lancet (2020) 395:507–13. Patients. New Microbes New Infect (2021) 43:100922. doi: 10.1016/
doi: 10.1016/S0140-6736(20)30211-7 j.nmni.2021.100922
14. Zhou M, Zhang X, Qu J. Coronavirus Disease 2019 (COVID-19): A Clinical 33. Calderon M, Li A, Bazo-Alvarez JC, Dennis J, Baker KF, Schim van der Loeff
Update. Front Med (2020) 14:126–35. doi: 10.1007/s11684-020-0767-8 I, et al. Evaluation of Procalcitonin-Guided Antimicrobial Stewardship in
15. Orlandi D, Battaglini D, Robba C, Viganò M, Bergamaschi G, Mignatti T, Patients Admitted to Hospital With COVID-19 Pneumonia. JAC-
et al. COVID-19 Phenotypes, Lung Ultrasound, Chest Computed Antimicrobial Resist (2021) 3(3):dlab133. doi: 10.1093/jacamr/dlab133
Tomography, and Clinical Features in Critically Ill Mechanically 34. Ticinesi A, Nouvenne A, Prati B, Guida L, Parise A, Cerundolo N, et al. The
Ventilated Patients. Ultrasound Med Biol (2021) 41(12):3323–32. Clinical Significance of Procalcitonin Elevation in Patients Over 75 Years
doi: 10.1016/j.ultrasmedbio.2021.07.014. Old Admitted for COVID-19 Pneumonia. Mediators Inflamm (2021)
16. Pelosi P, Ball L, Barbas CSV, Bellomo R, Burns KEA, Einav S, et al. 2021:1–10. doi: 10.1155/2021/5593806
Personalized Mechanical Ventilation in Acute Respiratory Distress 35. Kåsine T, Dyrhol-Riise AM, Barratt-Due A, Kildal AB, Olsen IC, Nezvalova-
Syndrome. Crit Care (2021) 25:250. doi: 10.1186/s13054-021-03686-3 Henriksen K, et al. Neutrophil Count Predicts Clinical Outcome in
17. Gattinoni L, Chiumello D, Caironi P, Busana M, Romitti F, Brazzi L, et al. Hospitalized COVID-19 Patients: Results From the NOR-Solidarity Trial.
COVID-19 Pneumonia: Different Respiratory Treatments for Different J Intern Med (2021) 291(12):241–3. doi: 10.1111/joim.13377
Phenotypes? Intensive Care Med (2020) 46:1099–102. doi: 10.1007/s00134- 36. Ulloque-Badaracco JR, Ivan Salas-Tello W, Al-kassab-Có rdova A, Alarcó n-
020-06033-2 Braga EA, Benites-Zapata VA, Maguiña JL, et al. Prognostic Value of
18. Robba C, Battaglini D, Ball L, Patroniti N, Loconte M, Brunetti I, et al. Neutrophil-to-Lymphocyte Ratio in COVID-19 Patients: A Systematic
Distinct Phenotypes Require Distinct Respiratory Management Strategies in Review and Meta-Analysis. Int J Clin Pract (2021) 75:e14596.
Severe COVID-19. Respir Physiol Neurobiol (2020) 279:103455. doi: doi: 10.1111/ijcp.14596
10.1016/j.resp.2020.103455 37. Liu K, Yang T, Peng X, Lv S, Ye X, Zhao T, et al. A Systematic Meta-Analysis
19. Tonelli R, Marchioni A, Tabbì L, Fantini R, Busani S, Castaniere I, et al. of Immune Signatures in Patients With COVID-19. Rev Med Virol (2021)
Spontaneous Breathing and Evolving Phenotypes of Lung Damage in 31:e2195. doi: 10.1002/rmv.2195
Patients With COVID-19: Review of Current Evidence and Forecast of a 38. Iwamura APD, Tavares da Silva MR, Hümmelgen AL, Soeiro Pereira PV,
New Scenario. J Clin Med (2021) 10:975. doi: 10.3390/jcm10050975 Falcai A, Grumach AS, et al. Immunity and Inflammatory Biomarkers in
20. George PM, Wells AU, Jenkins RG. Pulmonary Fibrosis and COVID-19: COVID-19: A Systematic Review. Rev Med Virol (2021) 31:e2199.
The Potential Role for Antifibrotic Therapy. Lancet Respir Med (2020) doi: 10.1002/rmv.2199
8:807–15. doi: 10.1016/S2213-2600(20)30225-3 39. Gorog DA, Storey RF, Gurbel PA, Tantry US, Berger JS, Chan MY, et al.
21. Cione E, Siniscalchi A, Gangemi P, Cosco L, Colosimo M, Longhini F, et al. Current and Novel Biomarkers of Thrombotic Risk in COVID-19: A
Neuron-Specific Enolase Serum Levels in COVID-19 Are Related to the Consensus Statement From the International COVID-19 Thrombosis
Severity of Lung Injury. PLoS One (2021) 16:e0251819. doi: 10.1371/ Biomarkers Colloquium. Nat Rev Cardiol (2022), 1–21. doi: 10.1038/
journal.pone.0251819 s41569-021-00665-7
22. Topp G, Bouyea M, Cochran-Caggiano N, Ata A, Torres P, Jacob J, et al. 40. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of
Biomarkers Predictive of Extubation and Survival of COVID-19 Patients. 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected
Cureus (2021) 13:e15462. doi: 10.7759/cureus.15462 Pneumonia in Wuhan, China. JAMA (2020) 323:1061. doi: 10.1001/
23. Alay H, Laloglu E. The Role of Angiopoietin-2 and Surfactant Protein-D jama.2020.1585
Levels in SARS-CoV-2-Related Lung Injury: A Prospective, Observational, 41. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical Course and Risk
Cohort Study. J Med Virol (2021) 93:6008–15. doi: 10.1002/jmv.27184 Factors for Mortality of Adult Inpatients With COVID-19 in Wuhan, China:
̇ Yılmaz S, Kızıltunç A. Evaluation of the Relationship
24. Kerget F, Kerget B, Iba A Retrospective Cohort Study. Lancet (2020) 395:1054–62. doi: 10.1016/
Between TREM-1/TREM-2 Ratio and Clinical Course in COVID-19 S0140-6736(20)30566-3
Pneumonia. Int J Clin Pract (2021) 75(10):e14697. doi: 10.1111/ijcp.14697 42. Yang J, Zheng Y, Gou X, Pu K, Chen Z, Guo Q, et al. Prevalence of
25. Martinez Mesa A, Cabrera Cé sar E, Martı́n-Montañez E, Sanchez Alvarez E, Comorbidities and its Effects in Patients Infected With SARS-CoV-2: A
Lopez PM, Romero-Zerbo Y, et al. Acute Lung Injury Biomarkers in the Systematic Review and Meta-Analysis. Int J Infect Dis (2020) 94:91–5.
Prediction of COVID-19 Severity: Total Thiol, Ferritin and Lactate doi: 10.1016/j.ijid.2020.03.017
Dehydrogenase. Antioxidants (2021) 10:1221. doi: 10.3390/antiox10081221 43. Zhu Z, Wang M, Lin W, Cai Q, Zhang L, Chen D, et al. Cardiac Biomarkers,
26. V’kovski P, Kratzel A, Steiner S, Stalder H, Thiel V. Coronavirus Biology and Cardiac Injury, and Comorbidities Associated With Severe Illness and
Replication: Implications for SARS-CoV-2. Nat Rev Microbiol (2021) Mortality in Coronavirus Disease 2019 (COVID-19): A Systematic Review
19:155–70. doi: 10.1038/s41579-020-00468-6 and Meta-Analysis. Immun Inflammation Dis (2021) 9(4):1071–100.
27. Rouse BT, Sehrawat S. Immunity and Immunopathology to Viruses: What doi: 10.1002/iid3.471
Decides the Outcome? Nat Rev Immunol (2010) 10:514–26. doi: 10.1038/ 44. Schiavone M, Gobbi C, Biondi-Zoccai G, D’Ascenzo F, Palazzuoli A,
nri2802 Gasperetti A, et al. Acute Coronary Syndromes and Covid-19: Exploring
28. Hamming I, Timens W, Bulthuis M, Lely A, Navis G, van Goor H. Tissue the Uncertainties. J Clin Med (2020) 9:1683. doi: 10.3390/jcm9061683
Distribution of ACE2 Protein, the Functional Receptor for SARS 45. Nishiga M, Wang DW, Han Y, Lewis DB, Wu JC. COVID-19 and
Coronavirus. A First Step Understanding SARS Pathogen J Pathol (2004) Cardiovascular Disease: From Basic Mechanisms to Clinical Perspectives.
203:631–7. doi: 10.1002/path.1570 Nat Rev Cardiol (2020) 17:543–58. doi: 10.1038/s41569-020-0413-9
29. Ippolito M, Misseri G, Catalisano G, Marino C, Ingoglia G, Alessi M, et al. 46. Jabri A, Kalra A, Kumar A, Alameh A, Adroja S, Bashir H, et al. Incidence of
Ventilator-Associated Pneumonia in Patients With COVID-19: A Stress Cardiomyopathy During the Coronavirus Disease 2019 Pandemic.
Systematic Review and Meta-Analysis. Antibiotics (2021) 10:545. JAMA Netw Open (2020) 3:e2014780. doi: 10.1001/jamanetworkopen.
doi: 10.3390/antibiotics10050545 2020.14780
30. Ippolito M, Simone B, Filisina C, Catalanotto FR, Catalisano G, Marino C, 47. De Marzo V, Di Biagio A, Della Bona R, Vena A, Arboscello E, Emirjona H,
et al. Bloodstream Infections in Hospitalized Patients With COVID-19: A et al. Prevalence and Prognostic Value of Cardiac Troponin in Elderly
Systematic Review and Meta-Analysis. Microorganisms (2021) 9:2016. Patients Hospitalized for COVID-19. J Geriatr Cardiol (2021) 18:338–45.
doi: 10.3390/microorganisms9102016 doi: 10.11909/j.issn.1671-5411.2021.05.004
31. Shen Y, Cheng C, Zheng X, Jin Y, Duan G, Chen M, et al. Elevated 48. The European Society for Cardiology. ESC Guidance for the Diagnosis and
Procalcitonin Is Positively Associated With the Severity of COVID-19: A Management of CV Disease During the COVID-19 Pandemic. (2020).
Meta-Analysis Based on 10 Cohort Studies. Med (B Aires) (2021) 57:594. Avalable at: https://www.escardio.org/Education/Covid-19-and-Cardiology/
doi: 10.3390/medicina57060594 ESC-COVID-19-(update: 10 June 2020).

Frontiers in Immunology | www.frontiersin.org 9 April 2022 | Volume 13 | Article 857573

Battaglini et al. Biomarkers for Prognosis in COVID-19

49. Gilad V, De Marzo V, Guglielmi G, Della BR, Giovinazzo S, Pescetelli F, et al. Hospitalized Patients With COVID-19. PLoS One (2021) 16:e0256744.
Cardiac Point-of-Care Ultrasound in Hospitalized Coronavirus Disease- doi: 10.1371/journal.pone.0256744
2019 Patients: Findings and Association With Outcome. J Cardiovasc Med 67. Sui J, Noubouossie DF, Gandotra S, Cao L. Elevated Plasma Fibrinogen Is
(2022) 23:e3–7. doi: 10.2459/JCM.0000000000001177 Associated With Excessive Inflammation and Disease Severity in COVID-19
50. Metkus TS, Sokoll LJ, Barth AS, Czarny MJ, Hays AG, Lowenstein CJ, et al. Patients. Front Cell Infect Microbiol (2021) 11:734005. doi: 10.3389/
Myocardial Injury in Severe COVID-19 Compared With Non–COVID-19 fcimb.2021.734005
Acute Respiratory Distress Syndrome. Circulation (2021) 143:553–65. 68. Blot M, de Maistre E, Bourredjem A, Quenot J-P, Nguyen M, Bouhemad B,
doi: 10.1161/CIRCULATIONAHA.120.050543 et al. Specific Features of the Coagulopathy Signature in Severe COVID-19
51. Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, et al. Association of Cardiac Pneumonia. Front Med (2021) 8:675191. doi: 10.3389/fmed.2021.675191
Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, 69. Ferná ndez S, Moreno-Castaño AB, Palomo M, Martinez-Sanchez J,
China. JAMA Cardiol (2020) 5:802. doi: 10.1001/jamacardio.2020.0950 Torramadé -Moix S, Té llez A, et al. Distinctive Biomarker Features in The
52. Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al. Clinical Characteristics of Endotheliopathy of COVID-19 and Septic Syndromes. Shock (2021) 57
Coronavirus Disease 2019 in China. N Engl J Med (2020) 382:1708–20. (1):95–105. doi: 10.1097/SHK.0000000000001823. Online ahead of print.
doi: 10.1056/NEJMoa2002032 70. Billoir P, Alexandre K, Duflot T, Roger M, Miranda S, Goria O, et al.
53. Ni W, Yang X, Liu J, Bao J, Li R, Xu Y, et al. Acute Myocardial Investigation of Coagulation Biomarkers to Assess Clinical Deterioration in
Injury at Hospital Admission Is Associated With All-Cause Mortality in SARS-CoV-2 Infection. Front Med (2021) 8:670694. doi: 10.3389/
COVID-19. J Am Coll Cardiol (2020) 76:124–5. doi: 10.1016/ fmed.2021.670694
j.jacc.2020.05.007 71. Joly BS, Darmon M, Dekimpe C, Dupont T, Dumas G, Yvin E, et al.
54. Doyen D, Moceri P, Ducreux D, Dellamonica J. Myocarditis in a Patient Imbalance of Von Willebrand Factor and ADAMTS13 Axis Is Rather a
With COVID-19: A Cause of Raised Troponin and ECG Changes. Lancet Biomarker of Strong Inflammation and Endothelial Damage Than a Cause
(2020) 395:1516. doi: 10.1016/S0140-6736(20)30912-0 of Thrombotic Process in Critically Ill COVID-19 Patients. J Thromb
55. Cipriani A, Capone F, Donato F, Molinari L, Ceccato D, Saller A, et al. Haemost (2021) 19:2193–8. doi: 10.1111/jth.15445
Cardiac Injury and Mortality in Patients With Coronavirus Disease 2019 72. Ambrosino P, Calcaterra I, Molino A, Moretta P, Lupoli R, Spedicato GA,
(COVID-19): Insights From a Mediation Analysis. Intern Emerg Med (2021) et al. Persistent Endothelial Dysfunction in Post-Acute COVID-19
16:419–27. doi: 10.1007/s11739-020-02495-w Syndrome: A Case-Control Study. Biomedicines (2021) 9:957.
56. Lombardi CM, Carubelli V, Iorio A, Inciardi RM, Bellasi A, Canale C, et al. doi: 10.3390/biomedicines9080957
Association of Troponin Levels With Mortality in Italian Patients 73. Janneh AH, Kassir MF, Dwyer CJ, Chakraborty P, Pierce JS, Flume PA, et al.
Hospitalized With Coronavirus Disease 2019. JAMA Cardiol (2020) Alterations of Lipid Metabolism Provide Serologic Biomarkers for the
5:1274. doi: 10.1001/jamacardio.2020.3538 Detection of Asymptomatic Versus Symptomatic COVID-19 Patients. Sci
57. Cameli M, Pastore MC, Mandoli GE, D’Ascenzi F, Focardi M, Biagioni G, Rep (2021) 11:14232. doi: 10.1038/s41598-021-93857-7
et al. COVID-19 and Acute Coronary Syndromes: Current Data and Future 74. Razdan K, Singh K, Singh D. Vitamin D Levels and COVID-19
Implications. Front Cardiovasc Med (2021) 7:593496. doi: 10.3389/ Susceptibility: Is There Any Correlation? Med Drug Discov (2020)
fcvm.2020.593496 7:100051. doi: 10.1016/j.medidd.2020.100051
58. Chieffo A, Stefanini GG, Price S, Barbato E, Tarantini G, Karam N, et al. 75. Fakhroo AD, Al Thani AA, Yassine HM. Markers Associated With COVID-
EAPCI Position Statement on Invasive Management of Acute Coronary 19 Susceptibility, Resistance, and Severity. Viruses (2020) 13:45.
Syndromes During the COVID-19 Pandemic. Eur Heart J (2020) 41:1839– doi: 10.3390/v13010045
51. doi: 10.1093/eurheartj/ehaa381 76. Battaglini D, Robba C, Fedele A, Trancǎ S, Sukkar SG, Di Pilato V, et al. The
59. Chung MK, Zidar DA, Bristow MR, Cameron SJ, Chan T, Harding CV, et al. Role of Dysbiosis in Critically Ill Patients With COVID-19 and Acute
COVID-19 and Cardiovascular Disease. Circ Res (2021) 128:1214–36. Respiratory Distress Syndrome. Front Med (2021) 8:671714. doi: 10.3389/
doi: 10.1161/CIRCRESAHA.121.317997 fmed.2021.671714
60. Zinellu A, Sotgia S, Fois AG, Mangoni AA, Serum CK-MB. COVID-19 77. Alcá ntara-Alonso E, Molinar-Ramos F, Gonzá lez-Ló pez JA, Alcá ntara-
Severity and Mortality: An Updated Systematic Review and Meta-Analysis Alonso V, Muñoz-Pé rez MA, Lozano-Nuevo JJ, et al. High Triglyceride to
With Meta-Regression. Adv Med Sci (2021) 66:304–14. doi: 10.1016/ HDL-Cholesterol Ratio as a Biochemical Marker of Severe Outcomes in
j.advms.2021.07.001 COVID-19 Patients. Clin Nutr ESPEN (2021) 44:437–44. doi: 10.1016/
61. Zhan L, Liu Y, Cheng Y, Guo W, Yang J. Predictive Value of Neutrophil/ j.clnesp.2021.04.020
Lymphocyte Ratio (NLR) on Cardiovascular Events in Patients With 78. Tepasse P-R, Vollenberg R, Fobker M, Kabar I, Schmidt H, Meier JA, et al.
COVID-19. Int J Gen Med (2021) 14:3899–907. doi: 10.2147/IJGM.S317380 Vitamin A Plasma Levels in COVID-19 Patients: A Prospective Multicenter
62. Yu J-S, Chen R-D, Zeng L-C, Yang H-K, Li H. Myoglobin Offers Higher Study and Hypothesis. Nutrients (2021) 13:2173. doi: 10.3390/nu13072173
Accuracy Than Other Cardiac-Specific Biomarkers for the Prognosis of 79. Murai IH, Fernandes AL, Sales LP, Pinto AJ, Goessler KF, Duran CSC, et al.
COVID-19. Front Cardiovasc Med (2021) 8:686328. doi: 10.3389/ Effect of a Single High Dose of Vitamin D 3 on Hospital Length of Stay in
fcvm.2021.686328 Patients With Moderate to Severe COVID-19. JAMA (2021) 325:1053.
63. Garcı́a de Guadiana-Romualdo L, Martı́nez Martı́nez M, Rodrı́guez Mulero doi: 10.1001/jama.2020.26848
MD, Esteban-Torrella P, Herná ndez Olivo M, Alcaraz Garcı́a MJ, et al. 80. Zelzer S, Prüller F, Curcic P, Sloup Z, Holter M, Herrmann M, et al. Vitamin
Circulating MR-proADM Levels, as an Indicator of Endothelial D Metabolites and Clinical Outcome in Hospitalized COVID-19 Patients.
Dysfunction, for Early Risk Stratification of Mid-Term Mortality in Nutrients (2021) 13:2129. doi: 10.3390/nu13072129
COVID-19 Patients. Int J Infect Dis (2021) 111:211–8. doi: 10.1016/ 81. Beltrão FE de L, Beltrão DC de A, Carvalhal G, Beltrão FE de L, Brito A da S,
j.ijid.2021.08.058 da Capistrano KHR, et al. Thyroid Hormone Levels During Hospital
64. Sorrentino S, Cacia M, Leo I, Polimeni A, Sabatino J, Spaccarotella CAM, Admission Inform Disease Severity and Mortality in COVID-19 Patients.
et al. B-Type Natriuretic Peptide as Biomarker of COVID-19 Disease Thyroid (2021) 31:1639–49. doi: 10.1089/thy.2021.0225
Severity—A Meta-Analysis. J Clin Med (2020) 9:2957. doi: 10.3390/ 82. Battaglini D, Brunetti I, Anania P, Fiaschi P, Zona G, Ball L, et al.
jcm9092957 Neurological Manifestations of Severe SARS-CoV-2 Infection: Potential
65. Robba C, Battaglini D, Ball L, Valbusa A, Porto I, Della Bona R, et al. Mechanisms and Implications of Individualized Mechanical Ventilation
Coagulative Disorders in Critically Ill COVID-19 Patients With Acute Settings. Front Neurol (2020) 11:845. doi: 10.3389/fneur.2020.00845
Distress Respiratory Syndrome: A Critical Review. J Clin Med (2021) 83. Huth SF, Cho S-M, Robba C, Highton D, Battaglini D, Bellapart J, et al.
10:140. doi: 10.3390/jcm10010140 Neurological Manifestations of Coronavirus Disease 2019: A
66. Poudel A, Poudel Y, Adhikari A, Aryal BB, Dangol D, Bajracharya T, et al. Comprehensive Review and Meta-Analysis of the First 6 Months of
D-Dimer as a Biomarker for Assessment of COVID-19 Prognosis: D-Dimer Pandemic Reporting. Front Neurol (2021) 12:664599. doi: 10.3389/
Levels on Admission and Its Role in Predicting Disease Outcome in fneur.2021.664599

Frontiers in Immunology | www.frontiersin.org 10 April 2022 | Volume 13 | Article 857573

Battaglini et al. Biomarkers for Prognosis in COVID-19

84. Battaglini D, Santori G, Chandraptham K, Iannuzzi F, Bastianello M, 101. Tantry US, Bliden KP, Cho A, Walia N, Dahlen JR, Ens G, et al. First
Tarantino F, et al. Neurological Complications and Noninvasive Experience Addressing the Prognostic Utility of Novel Urinary Biomarkers
Multimodal Neuromonitoring in Critically Ill Mechanically Ventilated in Patients With COVID-19. Open Forum Infect Dis (2021) 8:ofab274.
COVID-19 Patients. Front Neurol (2020) 11:602114. doi: 10.3389/ doi: 10.1093/ofid/ofab274
fneur.2020.602114 102. Fukao Y, Nagasawa H, Nihei Y, Hiki M, Naito T, Kihara M, et al. COVID-19-
85. Barbosa-Silva MC, Lima MN, Battaglini D, Robba C, Pelosi P, Rocco PRM, Induced Acute Renal Tubular Injury Associated With Elevation of Serum
et al. Infectious Disease-Associated Encephalopathies. Crit Care (2021) Inflammatory Cytokine. Clin Exp Nephrol (2021) 25:1240–6. doi: 10.1007/
25:236. doi: 10.1186/s13054-021-03659-6 s10157-021-02101-z
86. Lee B, Newberg A. Neuroimaging in Traumatic Brain Imaging. NeuroRX 103. Gradin A, Andersson H, Luther T, Anderberg SB, Rubertsson S, Lipcsey M,
(2005) 2:372–83. doi: 10.1602/neurorx.2.2.372 et al. Urinary Cytokines Correlate With Acute Kidney Injury in Critically Ill
87. Reichard RR, Kashani KB, Boire NA, Constantopoulos E, Guo Y, Lucchinetti COVID-19 Patients. Cytokine (2021) 146:155589. doi: 10.1016/
CF. Neuropathology of COVID-19: A Spectrum of Vascular and Acute j.cyto.2021.155589
Disseminated Encephalomyelitis (ADEM)-Like Pathology. Acta 104. Wang RR, He M, Kang Y. A Risk Score Based on Procalcitonin for Predicting
Neuropathol (2020) 140:1–6. doi: 10.1007/s00401-020-02166-2 Acute Kidney Injury in COVID-19 Patients. J Clin Lab Anal (2021) 35:
88. Ameres M, Brandstetter S, Toncheva AA, Kabesch M, Leppert D, Kuhle J, e23805. doi: 10.1002/jcla.23805
et al. Association of Neuronal Injury Blood Marker Neurofilament Light 105. Alfano G, Ferrari A, Fontana F, Mori G, Ligabue G, Giovanella S, et al.
Chain With Mild-to-Moderate COVID-19. J Neurol (2020) 267:3476–8. Twenty-Four-Hour Serum Creatinine Variation Is Associated With Poor
doi: 10.1007/s00415-020-10050-y Outcome in the Novel Coronavirus Disease 2019 (COVID-19) Patients.
89. Kanberg N, Ashton NJ, Andersson L-M, Yilmaz A, Lindh M, Nilsson S, et al. Kidney Res Clin Pract (2021) 40:231–40. doi: 10.23876/j.krcp.20.177
Neurochemical Evidence of Astrocytic and Neuronal Injury Commonly 106. Morell-Garcia D, Ramos-Chavarino D, Bauça JM, Argente del Castillo P,
Found in COVID-19. Neurology (2020) 95:e1754–9. doi: 10.1212/ Ballesteros-Vizoso MA, Garcı́a de Guadiana-Romualdo L, et al. Urine
WNL.0000000000010111 Biomarkers for the Prediction of Mortality in COVID-19 Hospitalized
90. Paterson RW, Benjamin LA, Mehta PR, Brown RL, Athauda D, Ashton NJ, Patients. Sci Rep (2021) 11:11134. doi: 10.1038/s41598-021-90610-y
et al. Serum and Cerebrospinal Fluid Biomarker Profiles in Acute SARS- 107. Wang K, Qu M, Ding L, Shi X, Wang C, Cheng S, et al. Liver and Kidney
CoV-2-Associated Neurological Syndromes. Brain Commun (2021) 3: Function Biomarkers, Blood Cell Traits and Risk of Severe COVID-19: A
fcab099. doi: 10.1093/braincomms/fcab099 Mendelian Randomization Study. Front Genet (2021) 12:647303.
91. Kanberg N, Simré n J, Edé n A, Andersson L-M, Nilsson S, Ashton NJ, et al. doi: 10.3389/fgene.2021.647303
Neurochemical Signs of Astrocytic and Neuronal Injury in Acute COVID-19 108. Kumar- MP, Mishra S, Jha DK, Shukla J, Choudhury A, Mohindra R, et al.
Normalizes During Long-Term Follow-Up. EBioMedicine (2021) 70:103512. Coronavirus Disease (COVID-19) and the Liver: A Comprehensive
doi: 10.1016/j.ebiom.2021.103512 Systematic Review and Meta-Analysis. Hepatol Int (2020) 14:711–22.
92. Esenwa C, Cheng NT, Luna J, Willey J, Boehme AK, Kirchoff-Torres K, et al. doi: 10.1007/s12072-020-10071-9
Biomarkers of Coagulation and Inflammation in COVID-19–Associated 109. Romero-Cristó bal M, Clemente-Sá nchez A, Piñeiro P, Cedeño J, Rayó n L,
I s ch e m i c S tr o k e . S t r o k e ( 2 0 2 1 ) 5 2 : e 7 0 6 – 7 0 9 . d o i : 1 0 . 11 6 1 / del Rı́o J, et al. Possible Unrecognised Liver Injury Is Associated With
STROKEAHA.121.035045 Mortality in Critically Ill COVID-19 Patients. Ther Adv Gastroenterol (2021)
93. Goyal N, Sodani AK, Jain R, Ram H. Do Elevated Levels of Inflammatory 14:175628482110234. doi: 10.1177/17562848211023410
Biomarkers Predict the Risk of Occurrence of Ischemic Stroke in SARS- 110. Caterino M, Costanzo M, Fedele R, Cevenini A, Gelzo M, Di Minno A, et al.
CoV2 ?: An Observational Study. J Stroke Cerebrovasc Dis (2021) 30:106063. The Serum Metabolome of Moderate and Severe COVID-19 Patients
doi: 10.1016/j.jstrokecerebrovasdis.2021.106063 Reflects Possible Liver Alterations Involving Carbon and Nitrogen
94. Yassin A, Ghzawi A, Al-Mistarehi A-H, El-Salem K, Y Benmelouka A, M Metabolism. Int J Mol Sci (2021) 22:9548. doi: 10.3390/ijms22179548
Sherif A, et al. Mortality Rate and Biomarker Expression Within COVID-19 111. Lasso G, Khan S, Allen SA, Mariano M, Florez C, Orner EP, et al.
Patients Who Develop Acute Ischemic Stroke: A Systematic Review and Longitudinally Monitored Immune Biomarkers Predict the Timing of
Meta-Analysis. Futur Sci OA (2021) 7:FSO713. doi: 10.2144/fsoa-2021-0036 COVID-19 Outcomes. PLoS Comput Biol (2022) 18:e1009778.
95. Mete E, Sabirli R, Goren T, Turkcuer I, Kurt O, Koseler A. Association doi: 10.1371/journal.pcbi.1009778
Between S100b Levels and COVID-19 Pneumonia: A Case Control Study. 112. Smilowitz NR, Nguy V, Aphinyanaphongs Y, Newman JD, Xia Y, Reynolds
Vivo (Brooklyn) (2021) 35:2923–8. doi: 10.21873/invivo.12583 HR, et al. Multiple Biomarker Approach to Risk Stratification in COVID-19.
96. Benjamin LA, Paterson RW, Moll R, Pericleous C, Brown R, Mehta PR, et al. Circulation (2021) 143:1338–40. doi: 10.1161/CIRCULATIONAHA.120.053311
Antiphospholipid Antibodies and Neurological Manifestations in Acute
COVID-19: A Single-Centre Cross-Sectional Study. EClinicalMedicine Conflict of Interest: The authors declare that the research was conducted in the
(2021) 39:101070. doi: 10.1016/j.eclinm.2021.101070 absence of any commercial or financial relationships that could be construed as a
97. Faour WH, Choaib A, Issa E, El Choueiry F, Shbaklo K, Alhajj M, et al. potential conflict of interest.
Mechanisms of COVID-19-Induced Kidney Injury and Current
Pharmacotherapies. Inflammation Res (2022) 71:39–56. doi: 10.1007/ Publisher’s Note: All claims expressed in this article are solely those of the authors
s00011-021-01520-8 and do not necessarily represent those of their affiliated organizations, or those of
98. Legrand M, Bell S, Forni L, Joannidis M, Koyner JL, Liu K, et al. the publisher, the editors and the reviewers. Any product that may be evaluated in
Pathophysiology of COVID-19-Associated Acute Kidney Injury. Nat Rev this article, or claim that may be made by its manufacturer, is not guaranteed or
Nephrol (2021) 17:751–64. doi: 10.1038/s41581-021-00452-0 endorsed by the publisher.
99. Liu Y, Xia P, Cao W, Liu Z, Ma J, Zheng K, et al. Divergence Between Serum
Creatine and Cystatin C in Estimating Glomerular Filtration Rate of Copyright © 2022 Battaglini, Lopes-Pacheco, Castro-Faria-Neto, Pelosi and Rocco.
Critically Ill COVID-19 Patients. Ren Fail (2021) 43:1104–14. This is an open-access article distributed under the terms of the Creative Commons
doi: 10.1080/0886022X.2021.1948428 Attribution License (CC BY). The use, distribution or reproduction in other forums is
100. Yasar E, Ozger HS, Yeter HH, Yildirim C, Osmanov Z, Cetin TE, et al. Could permitted, provided the original author(s) and the copyright owner(s) are credited and
Urinary Kidney Injury Molecule-1 be a Good Marker in Subclinical Acute that the original publication in this journal is cited, in accordance with accepted
Kidney Injury in Mild to Moderate COVID-19 Infection? Int Urol Nephrol academic practice. No use, distribution or reproduction is permitted which does not
(2021) 54(3):627–36. doi: 10.1007/s11255-021-02937-0 comply with these terms.

Frontiers in Immunology | www.frontiersin.org 11 April 2022 | Volume 13 | Article 857573