Utility of cardiac bioenzymes in predicting cardiovascular outcomes in SARS-CoV-2

Table 1 Summary of studies characterizing the role of cardiac troponin

Study	Type of study	Location	Number of participants	Recommendation
Diagnostic and prognostic utility of troponin
Lala et al[14], 2020	Single center, Observational	New York	2736	cTn elevated in patients with primary cardiac etiology including MI. Other etiologies included arrythmias, HF, myocarditis and Takotsubu cardiomyopathy
Khaloo et al[15], 2022	Multicenter, Retrospective	Massachusetts	2450
Sandoval et al[17], 2020	Review			Serial cTn measurement aids in risk stratification
Almeida et al[18], 2020	Single center, Retrospective	Brazil	183	Elevated cTn measured within first 24 h is associated with worst prognosis. Increased need for MV
Maino et al[19], 2021	Single center, Retrospective	Italy	189
Arcari et al[20], 2020	Multicenter, Observational	Italy	111	cTn elevation correlated with poor prognosis and need for MV
Role in outcome and mortality
Scarl et al[21], 2021	Single center, Retrospective	Ohio	81	In patients with pre-existing comorbidities, CTnI elevation is associated with mortality
Lala et al[14], 2020	Single center, Observational	New York	2,736	Threefold increase in mortality in patients with cTnI three times the upper limit of normal
Mueller et al[22], 2021	Review			cTn elevation is associated with significant in hospital adverse events
Henein et al[23], 2021	Multicenter, Retrospective	International, mainly European	748
Kermali et al[24], 2020	Systematic review	China	607
Arcari et al[25], 2021	Multicenter, Retrospective	Italy	252	cTn significantly elevated in patients with pre-existing comorbidities, and is associated with increased mortality
Lombardi et al[26], 2020	Multicenter,Cross sectional	Italy	614	Elevation in cTn associated with mortality. 45.3% patients had elevated cTn and correlated with 71% increase in mortality, and a 2-fold increase in additional complications inlcuding sepsis, PE, AKI
Salvatici et al[27], 2020	Single center, Retrospective	Italy	523	cTnT and cTnI remain independent predictors of mortality even after adjusting for potential confounders
Al Abbasi et al[28], 2020	Single center, Retrospective	Florida	257	Elevated cTnI in the first 24 h of admission had a significantly higher in hospital mortality, with 89.7% negative predictive value

cTn: Cardiac troponin; cTnT: Troponin T; cTnI: Troponin I; HF: Heart failure; MV: Mechanical ventilation; PE: Pulmonary embolism; AKI: Acute kidney injury.

Table 2 Summary of studies characterizing the role of natriuretic peptides

Study	Type of study	Location	Number of participants	Recommendation
Diagnostic and prognostic utility of natriuretic peptides
Arcari et al[20], 2020	Multicenter, Observational	Italy	111	Positive correlation between the rise in NPs and COVID-19 disease severity. Half of these patients had their NP level above the upper limit of normal
Caro-Codón et al[40], 2021	Population	Spain	396	In patients with history of HF, elevation in NT-proBNP above the cut-off for normal suggested development of acute HF
Gao et al[41], 2020	Multicenter, Prospective	China	402	This study proposed a triple cut point strategy of NT-proBNP (HF unlikely if NT-proBNP < 300pg/L, grey zone 300-900 pg/L and HF likely if > 900 pg/L) for its role in developing acute HF and in determining prognosis. Thirty day mortality in HF group was 40.8%.
Sorrentino et al[42], 2020	Meta-analysis of 13 observational studies		2248	Natriuretic peptides have significant prognostic importance in predicting severity of COVID-19
Yoo et al[43], 2021	Single center, Retrospective cohort	New York	679	In patients without a history of HF, elevated admission NT-proBNP correlated with fewer hospital free, ICU free and ventilator free days compared to those with low NT-proBNP levels
Alvarez-Garcia et al[44], 2020	Single center, Retrospective	New York	6439	No difference identified in the level of NP and COVID-19 disease severity
Dawson et al[45], 2020	Meta-analysis	China	12 studies included
Abdeen et al[46], 2021	Single center, Retrospective	New Jersey	230
Role in outcome and mortality
Gao et al[48], 2020	Single center, Retrospective	China	102	Natriuretic peptides independently associated with in-hospital mortality in severe COVID-19 patients. The cut off value predicting in hospital death was 88.64 pg/mL with a 100% sensitivity and 66.7% specificity.
Caro-Codón et al[40], 2021	Population	Spain	396	Elevations in NP correlated with in-hospital mortality, even after adjusting for relevant confounders
Calvo-Fernández A et al[49], 2021	Single center, Retrospective	Spain	872	Natriuretic peptide elevation is independently related to death or mechanical ventilation in COVID-19 patients
Selcuk et al[50], 2021	Single center, Retrospective	Istanbul	137	Among patients who did not have a baseline diagnosis of HF, NPs were independent predictors of mortality. This study used a cut off threshold of 260pg/ml predicting an in-hospital mortality with 82% sensitivity and 93% specificity
Iorio et al[51], 2022	Multicenter, Retrospective observational	Italy	341	The level of NP elevation correlated with mortality. Cut off threshold used in this study is 2598 pg/L predicting a 30-d mortality with 91.7% sensitivity and an 80% specificity
Belarte-Tornero et al[52], 2021	Single center, Retrospective	Spain	129
Dalia et al[53], 2021	Systematic review	India	5967	Patients with fulminant COVID-19 and elevated NPs had an eight-fold increased risk of acute cardiac injury and death when compared to their counterparts
Pranata et al[54], 2020	Meta analysis		967	In patients with HF, natriuretic peptide elevation is associated with disease progression and mortality. This effect was seen even after adjustment for troponin and CKMB
Iorio et al[51], 2022	Multicenter, Retrospective observational	Italy	341	The combined effect of cTn and NT-proBNP was studied in COVID-19 patients. Irrespective of prior HF history, increased mortality was seen in patients with both biomarker elevation. In patients with only one biomarker elevation, case fatality higher in patients with NP elevation
Stefanini et al[55], 2020	Single center, Retrospective	Italy	397

NP: Natriuretic peptide; NT-proBNP: N terminal pro-brain natriuretic peptide; HF: Heart failure; cTn: Cardiac troponin; COVID-19: Corona virus disease 2019.

Table 3 Summary of studies characterizing the role of novel biomarkers in prognosis and outcomes in COVID-19

Biomarker in COVID	Study	Recommendation
Presepsin	Favaloro et al[73]	Presepsin elevation is a reliable biomarker in COVID-19
	Park et al[74]	A four-to-five-fold increase in presepsin correlates with disease severity in COVID-19
	Lippi et al[75]
	Koyjit et al[73]
	Fukada et al[77]	Presepsin is elevated in severe cases of SARS-CoV-2 associated respiratory complications
	Park et al[74]	Presepsin level at 717pg/ml is a significant predictor of 30-day mortality
	Dell’Aquila et al[79]	A threefold rise in presepsin has been identified as a very specific indicator of 30-day mortality
	Lippi et al[75]
Soluble ST2 (sST2)	Omland et al[87]	Robust association between baseline sST2 level and disease severity along with poor outcome
	Huang et al[88]	Baseline sST2 is associated with a worse prognosis
	Ragusa et al[89]	Circulating level of sST2 can be used as a discharge prognosticator
Galectin-3	Caniglia et al[96]	Gal-3 is considerably higher in bronchoalveolar immune cells in patients with severe COVID-19 disease
	Portacci et al[97]	Higher galectin-3 is associated with worse outcomes and shorter survival
Copeptin	Gregoriano et al[100]	Serum copeptin level above 20 Pmol/L had sensitivity of > 88% to predict severe COVID-19
	Hammad et al[101]	Serum copeptin level above 18.5 Pmol/L had sensitivity of > 93% and specificity of 100% to predict severe COVID-19
GDF 15	Apfel et al[103]	Higher levels of GDF-15 correlated with severity of COVID-19

Gal-3: Galectin-3; GDF-15: Growth differentiation factor 15; sST2: Soluble ST2.