Serum ferritin as an independent risk factor for severity in COVID-19 patients.

Dear Editor,

In this Journal, Li and colleagues recently reported that Serum Amyloid A is a biomarker of severe Coronavirus Disease and poor prognosis. Evidence shows that severe COVID-19 cases exhibit features of systemic inflammatory reactions, including hyperferritinemia. We conducted a retrospective study included 147 confirmed COVID-19 patients in Changsha, a non-epicenter city of China. The overall proportion of severe disease was 16.32% (24/147). Table 1 shows the differences in the baseline characteristics between severe and nonsevere COVID-19 patients. The severe patients had higher levels of serum ferritin than the nonsevere patients (Fig. 1 A). Multivariate logistic regression analysis indicated that the serum ferritin level on admission was an independent risk factor for disease severity in COVID-19 patients. CRP (OR=1.036; 95% CI 1.008 to 1.065; P = 0.012) and lymphocyte counts (OR=0.284; 95% CI 0.08 to 1.005; P = 0.051) were found to be two additional independent risk factors for disease severity through the multivariate logistic regression model. We found that higher serum ferritin was able to predict an increased risk of disease severity in patients with COVID-19 (Fig. 1 B). The levels of serum ferritin positively correlate with levels of CRP (r = 0.4142, P<0.0001) (Fig. 1 C), and inversely correlate with lymphocytic counts (r=−0.1841, P<0.03) (Fig. 1 D). These are two critical factors considered to be associated with the disease severity in patients with COVID-19. To our knowledge, this study is the first to study the epidemiologic impact of serum ferritin and to focus on the association between hyperferritinemia and disease severity in patients with COVID-19.

Table 1

Association between baseline variables and disease severity.

Variable	Severe (n = 24)	Nonsevere (n = 123)	P value
Age, years	52 (29–78)	40 (19∼81)	0.0011
Sex			0.4772
Male	10 (41.67%)	61 (49.59%)
Female	14 (58.33%)	62 (50.41%)
Hypertension			0.4385
Yes	4 (16.67%)	11 (8.94%)
No	20 (83.33%)	112 (91.06%)
Diabetes			0.4385
Yes	2 (8.33%)	6 (4.88%)
No	22 (91.67%)	117 (95.12%)
White blood cells, 109/l	5.12 (1.48∼8.27)	4.64 (1.75∼13.43)	0.6702
Neutrophils, 109/l	3.455 (0.911∼7.22)	2.84 (0.64∼9.96)	0.0373
Lymphocytes, 109/l	0.8 (0.421∼1.83)	1.35 (0.45∼3.67)	<0.0001
Hemoglobin, G/L	123.5 (70∼161)	130 (78∼170)	0.3536
Platelets, 109/l	159.5 (58∼423)	184 (31∼429)	0.2971
ALT, U/L	23.22 (8.9∼162.6)	20.13 (2.6∼140.9)	0.2972
AST, U/L	25.31 (12.64∼71.56)	22.88 (12.3∼236.9)	0.0719
Creatinine, μmol/L	49.15 (21.92∼255.7)	53.3 (20.58∼160.3)	0.2311
PT, s	12.1 (9.9∼19.6)	11.4 (9.1∼13.7)	0.1028
APTT, s	31.75 (21.3∼38.5)	32.4 (20.6∼51.4)	0.1654
D-dimer, μg/L	0.575 (0.06∼7.79)	0.2186 (0.01∼4.15)	0.0003
LDH, U/L	209.6 (124.4∼365.6)	150.8 (16.2∼287.2)	0.0002
C-reactive protein, mg/L	38.05 (2.81∼88.19)	12.25 (0.2∼78.07)	<0.0001
Procalcitonin, ng/mL			0.006
< 0.5	10 (41.67%)	87 (70.73%)
≥ 0.5	14 (58.33%)	36 (29.27%)
Serum ferritin, µg/L	733.1 (65.34∼>2000)	296.4 (9.51∼1568)	<0.0001

Data are median (range), or n (%). ALT: alanine aminotransferase, AST: aspartate aminotransferase,.

PT: prothrombintime, APTT: activated partial thromboplastin time, LDH: lactate dehydrogenase.

Fig. 1

Serum ferritin levels of COVID-19 patients and its correlation with the disease severity. A Serum ferritin levels on admission in severe and nonsevere COVID-19 patients (P< 0.0001). B ROC curve of serum ferritin for the severity of COVID-19. Correlations between serum ferritin and C-reactive protein (C), lymphocyte (D).

Wu et al. investigated 201 confirmed cases of COVID-19 to study the clinical characteristics and outcomes in patients with COVID-19 pneumonia who developed acute respiratory distress syndrome (ARDS) or died; their findings showed that higher serum ferritin was an independent risk factor associated with ARDS development. Another meta-analysis also recommended serum ferritin as a candidate variable for risk stratification models that may serve as clinical predictors of severe and fatal COVID-19. In our study, when patients were grouped according to the serum ferritin level with a cut off of 500 ng/ml derived from the HLH-2004 criterion, hyperferritinemia accounted for 29.93% (44/147) of patients. The hyperferritinemia group had a higher proportion of severe cases (31.82% vs. 9.71%, P = 0.0009) and bilateral pulmonary infiltration rate (95.45% vs. 79.61%, P = 0.0297) than patients without hyperferritinemia. Hyperferritinemic COVID-19 patients were older and more likely to be male. Moreover, these patients had significantly higher levels of serum creatine, ALT, AST and LDH, lower levels of lymphocytes, and significantly higher levels of inflammatory markers, such as CRP, PCT and d-dimer, than the patients in the nonhyperferritinemia group. All these indicators have been reported as warning parameters for severe or critical COVID-19 patients. In addition, these correlations may indicate that patients with hyperferritinemia tend to have more severe disease than those without hyperferritinemia. Multivariate logistic regression models were adjusted for several disease-related risk factors at admission, including age, neutrophil count, lymphocyte count, d-dimer, LDH, C-reactive protein, and procalcitonin, the analysis found that the serum ferritin level was an independent risk factor for disease severity in COVID-19 patients (OR = 3.302, 95% CI, 1.141∼9.553, P = 0.028). And ROC curve study confirmed the predictive value of serum ferritin (AUC = 0.7480, P <0.001).

Serum ferritin is an iron storage protein that is widely measured as an indicator of iron status, but it is also a well-known inflammatory marker. Serum ferritin levels can be increased significantly in response to inflammation and a variety of diseases. As early as 1997, Connelly et al. investigated serum ferritin levels in patients at risk for and with ARDS and found serum ferritin to be a predictor of ARDS. Lagan et al. even found different genetic profiles of the genes involved in the processing and storage of cellular iron between patients with ARDS and healthy control subjects. Garcia et al. found that ferritin >500 ug/L was associated with the most severe outcomes in children with severe sepsis and septic shock. Consistent with these reports, our study also found that patients with hyperferritinemia (≥500 ug/L) were more likely to progress with bilateral pulmonary infiltration and a more severe disease course. In addition, there are a series of diseases whose presence or severity is known to be related to serum ferritin levels, i.e., amyotrophic lateral sclerosis (ALS), atherosclerosis (AS), systemic lupus erythematosus (SLE) and so on. Therefore, since the serum ferritin level is correlated with the degree of systemic and pulmonary inflammation, it is reasonable that hyperferritinemia is associated with disease severity in patients with COVID-19.

The mechanisms responsible for the association of hyperferritinemia and disease severity in patients with COVID-19 are unclear, but there are several possibilities for this phenomenon: 1) proinflammatory cytokines such as interleukin-Iβ (IL-lβ), tumor necrosis factor-a (TNF-α), and IL-6 may increase ferritin synthesis. Hence, we speculated that SARS-CoV-2-induced production of proinflammatory cytokines (i.e., IL-6, TNF-α), which are known to be elevated in COVID-19, might promote ferritin synthesis early in inflammation. 2) The cellular damage derived from inflammation can promote the leakage of intracellular ferritin, thus elevating serum ferritin. 3) In acidosis, the microvascular environment and increased production of reactive oxygen species (ROS) might liberate iron from ferritin, and it is this unliganded iron that can participate in Haber-Weiss and Fenton reactions, creating hydroxyl radicals, causing further cellular damage, and worsening tissue injury, thus causing a vicious cycle of inflammation. Similarly, one study found that the assembly of Middle East Respiratory Syndrome (MERS) coronavirus nanoparticles is related to chaperone-mediated ferritin. However, further investigations are needed to confirm the role of serum ferritin levels in the pathogenesis of COVID-19.

In conclusion, this retrospective study performed in a Chinese population demonstrated that a high level of serum ferritin is an independent risk factor for the severity of COVID-19. Assessing serum ferritin levels during hospitalization may be important to recognize high-risk individuals with COVID-19.

Funding

This work was funded by the , Grant No. 81974000.

Declaration of Competing Interest

The authors state that they have no conflicts of interest to disclosure.