Heme catabolic biomarker levels among sepsis, no sepsis, and control groups

We divided 156 patients with COVID-19 of at least moderate severity into the following groups: sepsis (n = 71), no sepsis (n = 85), and healthy controls (n = 100). Heme values in the sepsis, no sepsis, and control groups were 86.3 ± 116.5, 86.2 ± 88.3, and 39.7 ± 19.2 µM, respectively; p < 0.001 (Fig. 2). A post hoc analysis indicated that heme values were significantly higher in the sepsis and no-sepsis groups compared with the control group (p < 0.001). HO-1 values in the sepsis, no sepsis, and control groups were 39.9 ± 53.0, 17.7 ± 13.0, and 8.8 ± 4.2 ng/mL, respectively; p < 0.001. In a post hoc analysis for HO-1, the sepsis group had significantly higher values than those observed in the no sepsis and control groups (p < 0.001). Heme and HO-1 levels differed significantly between patients with COVID-19 and those in the control group.

Fig. 2

Influence of coronavirus disease (COVID-19) infection on patients' heme catabolism. A Heme and B HO-1. p-values calculated using a Student’s t-test are shown above the scatter points. ***Indicates p < 0.001 for the difference between paired scatter points, respectively

Baseline characteristics are shown in Table 1. No significant differences were found between the sepsis and no-sepsis groups in terms of SARS-CoV-2 CtV, BMI, initial body temperature, respiratory rate, heart rate, GCS, diabetes mellitus, neurologic disease, chronic kidney disease, chronic liver disease, malignancy, and autoimmune disease. However, there were significant differences between the sepsis and no-sepsis groups regarding older age (64.7 vs. 54.7 years, p < 0.001), male sex (62.0% vs. 43.5%, p = 0.022), lower initial mean MAP (90.3 vs. 97.3 mmHg, p = 0.002), SpO2% (90.5% vs. 94.4%, p = 0.002), higher CCI (3.13 vs. 2.12, p = 0.001), higher cardiovascular disease comorbidity (35.2% vs. 16.5%, p = 0.007), higher pulmonary disease comorbidity (12.7% vs. 3.5%, p = 0.039), higher initial qSOFA (0.41 vs. 0.14, p = 0.002), and higher initial CURB-65 score (1.82 vs. 0.45, p < 0.001), respectively.

Table 1 Comparison of study participant characteristics (n = 156)Laboratory data

Comparisons of blood test results between patients in the sepsis and no-sepsis groups are shown in Table 2. No differences in red blood cell count, or in hemoglobin, monocyte, serum glutamic pyruvic transaminase, alkaline phosphatase, creatinine phosphokinase, prothrombin time, international normalized ratio, activated partial thromboplastin clotting time (aPTT), heme, or total bilirubin levels were observed between the sepsis and no-sepsis groups. However, comparison of the sepsis group with the no-sepsis group showed that the sepsis group higher white blood cell (7.78 vs. 6.05 103/µL, p = 0.004); lower platelet (196.8 vs. 248.2 103/µL, p = 0.001), higher neutrophil (6.40 vs. 4.13 103/µL, p < 0.001), and lower lymphocyte (0.80 vs. 1.43 103/µL, p < 0.001) counts, and lower sodium (135.1 vs. 136.9 mEq/L, p = 0.002), higher potassium (3.9 vs. 3.7 mEq/L, p = 0.028), higher serum glutamic oxaloacetic transaminase (SGOT) (41.9 vs. 29.3 U/L, p = 0.004), lower albumin (3.39 vs. 3.91 g/dL, p < 0.001), higher BUN (26.1 vs. 13.3 mg/dL, p < 0.001), higher creatinine (1.42 vs. 0.76 mg/dL, p = 0.017), higher random glucose (170.5 vs. 124.2 mg/dL, p = 0.001), higher CRP (8.46 vs. 3.12 mg/dL, p < 0.001), higher lactate dehydrogenase (442.0 vs. 251.8 U/L, p < 0.001), and higher d-dimer (3648.0 vs. 631.7, p < 0.001) levels. In comparison, concerning HO-1 catabolism biomarkers, including HO-1, those in the sepsis group had higher HO-1 catabolism biomarkers than those in the no-sepsis group (42.1 vs. 15.8 ng/mL, respectively; p < 0.001) and ferritin (752.4 vs. 493.6 ng/mL, respectively; p = 0.006) (Fig. 2, Table 2). However, no significant differences were observed in terms of heme and total bilirubin levels between the two groups.

Table 2 A comparison of blood test results in patients with COVID-19 (n = 156)Clinical outcomes

Patients in the sepsis group had poorer clinical outcomes than those in the no-sepsis group (Table 3). Based on the final COVID-19 severity definition, those in the sepsis group had significantly worse critical illness compared with those in the no-sepsis group (78.9% vs. 0%, p < 0.001), more hospitalization days (27.5 vs. 16.2, p < 0.001), greater circulation dysfunction (12.7% vs. 0%, p = 0.001), greater respiratory dysfunction (81.7% vs. 0%, p < 0.001), greater renal dysfunction (29.6% vs. 2.4%, p < 0.001), greater hematologic dysfunction (39.4% vs. 14.1%, p < 0.001), greater septic shock (8.5% vs. 0%, p = 0.008), higher 48-h SOFA scores (4.28 vs. 0.21, p < 0.001), and lower survival rates (64.8% vs. 100.0%, p < 0.001), respectively.

Table 3 A comparison of the clinical outcomes between sepsis and no-sepsis groups (n = 156)Factors associated with 48-h sepsis in patients with at least moderate COVID-19-related pneumonia

The multivariable logistic regression analysis was forward conditionally adjusted for all the variables with p < 0.05 in the comparisons between the sepsis and no-sepsis groups. The adjusted factors were initial CURB-65 (adjusted odds ratio [aOR] 5.331, 95% confidence interval [CI] 2.587–10.987; p < 0.001), albumin (aOR 0.139, 95% CI 0.003–0.636; p = 0.01), d-dimer (aOR 1.001, 95% CI 1.000–1.002; p = 0.032), and HO-1 (aOR 1.116, 95% CI 1.055–1.180; p < 0.001) levels; these factors were significantly associated with 48-h sepsis episodes (Table 4).

Table 4 Logistic regression models of sepsis factors (n = 156)

Furthermore, the multivariable linear regression analysis was adjusted stepwise for all independent variables (p < 0.05) to predict the dependent variable 48-h SOFA scores. Finally, initial CURB-65, d-dimer, aPTT, BMI, creatinine, SpO2, CRP, and HO-1 levels were significantly associated with the 48-h SOFA score, as shown in Table 5.

Table 5 Multiple linear regression models of 48-h SOFA score factors (n = 156)

In the sepsis subgroup analysis, those who survived had significantly lower HO-1 levels than those who did not survive (30.5 vs. 63.5 ng/mL, respectively; p = 0.042). There was no significant difference between patients who survived and those who did not in terms of heme, total bilirubin, and ferritin levels. Further evaluation in the multivariable Cox regression analysis (Table 6) showed that CCI [adjusted hazard ratio (aHR) = 1.659, 95% CI 1.283–2.145, p < 0.001], initial CURB-65 [aHR = 2.000, 95% CI 1.238–3.231, p = 0.005], and 48-h SOFA score [aHR = 1.730, 95% CI 1.353–2.210, p < 0.001] increased the hazard of in-hospital mortality. However, HO-1 did not significantly increase the hazard of in-hospital mortality in moderate-to-critical COVID-19.

Table 6 Cox regression model after adjusting for other confounding factors