**7.2 GDF-15—growth differentiation factor 15**

Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor β superfamily and is widely distributed in low concentrations in most organs [12]. Physiological GDF-15 concentrations increase with age, while the expression is upregulated in pathological states through several pathways that mediate damage to the heart, lungs, liver, and kidneys including inflammation, oxidative stress, and hypoxia. Elevated concentrations of circulating GDF-15 have been identified in multiple disease entities like CVD, sepsis, cancer, and diabetes. GDF-15 levels seem to be a robust predictor of disease progression.

A clinical trial from Norway in 2020 looked at the value of GDF-15 as a biomarker in 123 patients admitted with COVID-19, GDF-15 was elevated in 80% of patients hospitalized with COVID-19, and higher concentrations were associated with SARS-CoV-2 viremia, hypoxemia, and worse clinical outcome. Moreover, GDF15 concentrations were more closely associated with poor outcomes than established biomarkers in COVID-19, including cTnT, NT-proBNP, CRP, and D-dimer. Greater increases in GDF-15 during hospitalization were also independently associated with worse outcomes.

#### **7.3 Cardiac enzymes and prognosis**

The prognostic role of cardiac markers in patients hospitalized with COVID-19 is remarkably similar to those in patients with viral pneumonia due to influenza, as well as for pneumonia and ARDS in general in addition to certain unique characteristics. Increased concentrations of cTn, hs-TnI, pro-BNP have been showed to have a correlation with increased mortality and severity of COVID-19 pneumonia [13]. Mild elevations in cardiac troponin concentrations, particularly in older patients with pre-existing cardiac disease, are often explained by the combination of known or unknown pre-existing cardiac disease and acute myocardial injury related to COVID-19 or any pneumonia [14, 15]. It is imperative to be aware of the potential use of anticoagulants and anti-cytokine therapies as conceivable therapeutic options, which need to be further explored in clinical trials. In such cases, when there is evidence of cardiac injury as indicated by elevated troponins, possibilities such as myocardial microthrombi should be considered. In patients with established or suspected COVID-19 normal hs-cTnT/I and BNP/NT-proBNP concentrations, of course always in conjunction with vital parameters including pulse oximetry, can reassure physicians that outpatient management is feasible [16]. These insights can help overcome the limitations in determining the prognosis and stratification of patients as well as predicting their mortality. The cardiovascular system has been shown to be a major contributor to the proportion of deaths classified as "noncardiovascular" by current classification schemes. An example of this is severe sepsis, mortality rates of which have a high contribution from dysfunction of the cardiac system, determined by the enzymes discussed above. Various other cardiac and vascular biomarkers are being studied in ongoing COVID-19 research. An example of this is the emerging data that growth differentiation factor 15 (GDF-15), a member of the transforming growth factor β superfamily that is released by stress due to change in hemodynamics as well as inflammation has better prognostic accuracy than established biomarkers in patients with COVID-19.

#### **8. Limitations**

Cardiac troponin provides incremental prognostic information, only in addition to other routinely available variables. These include vital signs, clinical judgment, and other inflammatory markers such as C-reactive protein and D-dimer. Moreover, the increased implementation of these markers, such as elevated cardiac troponin in routine practice might result in inappropriate diagnostic and therapeutic interventions [17]. For example, some clinicians may elect to perform a coronary angiography in the setting of an isolated cardiac troponin elevation. These elevations would likely be in the setting of supply-demand imbalance, and less likely due to type 1 acute myocardial injury. These increased interventions also serve as a possible cause for increased harm to patients as well as the medical care team due to increased exposure to COVID-19 patients. Even non-invasive investigations may be associated with the harm caused due to the risk associated with unnecessarily transporting critically ill patients through the hospital. Hence, firm indications for testing are advocated for [18]. However, when appropriate indications are present, one should not withhold essential evaluations. There is concern that measuring cardiac troponin during the initial blood sampling in the ED may delay patient disposition, as elevated levels require additional investigation, and possibly consultation. In patients with COVID-19 and patients with ARDS, there is currently no evidence that any intervention triggered by an elevation in cardiac troponin concentration will have an impact on patient outcomes.
