Growth differentiation factor 15 as an emerging novel biomarker in SARS-CoV-2 infection

Table 1 Studies included in the systematic review, with duration, type, region/place, and main findings

Refs	Study duration	Type of study	Region/place	Main findings
Myhre et al[23], 2020	March 18, 2020 to May 4, 2020	Prospective, observational study	Norway	GDF-15 has a better prognostic significance than recognized inflammatory biomarkers like CRP, ferritin, procalcitonin, and IL-6
Notz et al[24], 2020	March 14 to May 28, 2020	A single-center retrospective study	Germany	There was no evident imbalance of pro-and anti-inflammatory pathways, with higher GDF-15 levels in patients with SARS-CoV-2 infection during ICU stay, implying elevated tissue resilience
Luis García de Guadiana Romualdo et al[25], 2021	March 14 to April 12, 2020	Case-series	Spain	The GDF level was significantly high in nonsurvivors compared to survivors of SARS-CoV-2 infection, and it may be useful to predict prognosis
Teng et al[26], 2021	January 22, 2020, to May 13, 2020	Retrospective study	China	GDF-15 could be used as a biomarker to predict the severity of SARS-CoV-2 infection. GDF-15 level increased consistently with increased severity of SARS-CoV-2 infection, and GDF-15 expression returned to normal level similarly in a convalescent group compared to the healthy control participants. Hence, it implies that the GDF-15 precisely monitors the progression of SARS-CoV-2 infection
Kanberg et al[27], 2021	February 21 to November 5, 2020	Prospective study	Sweden	Patients with severe and moderate SARS-CoV-2 infection exhibited significantly increased GDF-15 levels compared with participants with mild infection and controls throughout the acute phase. Even after 6 mo of infection, GDF-15 concentrations persisted considerably higher in the severe and moderate infections compared to patients with mild infection and controls
Ebihara et al[28], 2022	August 2020 to December 2020	Prospective multicenter observational study	Japan	GDF-15 may be beneficial to predict delayed recovery or mortality of SARS-CoV-2-infected patients during ICU treatment
Alserawan et al[29], 2021	Not mentioned	Prospective study	Spain	GDF-15 may play a role in categorizing SARS-CoV-2-infected patients based on severityGDF-15 is an excellent biomarker to detect impaired respiratory function compared to CRP and D-dimer

CRP: C-reactive protein; GDF-15: Growth differentiation factor 15; IL-6: Interleukin 6; ICU: Intensive care unit; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.

Table 2 Review of data extracted for growth differentiation factor 15 in SARS-CoV-2 infection from included studies

Refs		Myhre et al[23], 2020	Notz et al[24], 2020	Luis García de Guadiana Romualdo et al[25], 2021	Teng et al[26], 2021	Kanberg et al[27], 2021	Ebihara et al[28], 2022	Alserawan et al[29], 2021
Sample size and subgroup of participants, if any		123 confirmed cases of SARS-CoV-2 infection (non-ICU survivor = 88, ICU admission/ death = 28)	13 cases of SARS-CoV-2 infection with ARDS	66 confirmed cases of SARS-CoV-2 infection (non-survival = 58, survival = 6)	111 confirmed cases of SARS-CoV-2 infection and 20 healthy controls (asymptomatic = 14, mild = 12, moderate = 34, severe = 18, and convalescent = 33)	100 confirmed cases of SARS-CoV-2 infection (mild = 24, moderate = 28, severe = 48] and 51 healthy controls	306 confirmed cases of SARS-CoV-2 infection	84 confirmed cases of SARS-CoV-2 infection and 20 healthy controls
GDF-15 level in pg/mL	Healthy controls				13.5 (8.0–79.0)	703.0 (501.0–949.0)	-	582.0 (370.0-807.0)
	Mild				136.4 (44.7–321.4)	748.0 (586.0–1087.0)	-	2051.0 (1474.0-2925.0)
	Moderate		12400.0		256.2 (76.1–341.0)	3450.0 (2337.0–4105.0)	-
	Severe			-	524.8 (405.1–831.1)	3562.0 (2458.0–5880.0)	Increased during ICU stay
	Critical				621.0	-	-	-
	Non-ICU survivor	2187.0 (1344.0-3620.0)	-	2590.0 (1886.0-4811.0)	-	-	-
	ICU admission or death	4225.0 (3197.0-5972.0)	-	9448.0 (6462.0-11707.0)	-	-	-	-
AUC and 95% CI of GDF-15 in ROC analysis		0.78 (0.70–0.86) P < 0.001	Not mentioned	0.89 (0.792–0.955) P < 0.001	0.89	Not mentioned	For severity: 0.764; For prognosis: 0.740	0.729 (0.602-0.857) P = 0.002
The optimal cut-off value of GDF-15		2252.0 pg/mL, to differentiate non-ICU survivors and ICU admission or death	Not mentioned	7789.00 pg/mL, to differentiate non-ICU survivors and ICU admission or death	Not mentioned	Not mentioned	Not mentioned	1675.0 pg/mL, to recognize deprived respiratory function (SpO2/FiO2 ≤ 400)
Method of GDF-15 measurement		ELISA	ELISA	Electro-chemiluminescent	ELISA	Electro-chemiluminescent	ELISA	ELISA
Additional findings related to GDF-15		It was associated with viral load and hypoxemia. Better prognostic significance compared to CRP, ferritin, IL-6, and procalcitonin	It was not correlated with age and BMI	Positively correlated with CRP, ferritin, and D-dimer	GDF-15 indicates the severity and closely monitor the progression of SARS-CoV-2	Elevated GDF-15 was significantly related to hypoxemia, viral load, and worse clinical consequences	The plasma level of GDF-15 was significantly associated with the time to wean-off mechanical ventilation	Positively correlated with CRP, D-dimer, and neutrophil count and negatively correlated with lymphocyte count

ARDS: Acute respiratory distress syndrome; BMI: Body mass index; CRP: C-reactive protein; ELISA: Enzyme-linked immunosorbent assays; GDF-15: Growth differentiation factor 15; IL-6: Interleukin 6; ICU: Intensive care unit; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.