Demographic and clinical characteristics of patients with COVID-19/HBV co-infected
A total of 5447 adult patients with confirmed COVID-19 were screened, we excluded 820 without results of HBV serological marker test. Among 4627 remainders, 190 patients were HBsAg-positive. The prevalence of HBV co-infection in hospitalized COVID-19 patients was 4.1% (Figure 1).
Of the 190 cases with COVID-19 and HBV co-infection, 105 fulfilled the definition of severe COVID-19. The incidence of severe cases in COVID-19 and HBV co-infection patients was 55.26%. One-hundred five patients with COVID-19 and HBV co-infection were categorized according to corticosteroid treatment (n=55) or non-corticosteroid treatment (n=50) (Figure 1).
Baseline characteristics were similar in the two groups and the median age was 62.0 years (IQR 54.0–71.0). Sixty (57.1%) patients were male. Fifteen patients had pre-existing cirrhosis. A majority of patients were tested negative for HBeAg (95.2%). The incidence of HBeAb positive was 17.1% (18/105) (Table 1).
A higher proportion of patients in the corticosteroids group than in non-corticosteroid group received anticoagulant therapy (29.1% VS 10.0%, P = 0.015) (Table 1).
Baseline laboratory findings according to corticosteroid treatment
The baseline laboratory testing results on admission were displayed in Table 2. There was no significant difference between corticosteroids treated and corticosteroids free patients for laboratory findings including leukocytes and platelets counts, and plasma levels of D-dimer, ALT, AST, ALP, bilirubin, pre-albumin, albumin, total cholesterol, triglyceride, high density lipoprotein, high-sensitivity troponin, high sensitivity C-reactive protein (HS-CRP), IL-6 and procalcitonin (PCT) (all P >0.05). In addition, SOFA and APACHE II scores at baseline were not statistically different between the two groups (all P > 0.05) (Table 2).
Effects of corticosteroid treatment in critically ill patient with COVID-19 and HBV co-infection
Effects on laboratory parameters
As compared to corticosteroids-free patients, corticosteroids treated patients had significantly increased neutrophils counts and D-dimer levels after received corticosteroids (time points were 14 days, 28 days after admission respectively) (all P<0.05) (Figure 2C, 2F). ALT, bilirubin and IL-6 level had no significant difference during corticosteroid treatment (time points were 7 days, 14 days, and 28 days after admission respectively) (all P > 0.05) (Figure 2A, 2B, 2E).
Effects on clinical course and outcomes
There was no significant difference between corticosteroids treated and corticosteroids free patients on clinical course, according to the incidence of sepsis shock, acute live injury, AKI and acute cardiac injury (all P > 0.05) (Table 3).
More patients had SARS-CoV-2 RNA positive result in upper respiratory tract more than 20 days after symptoms onset in patients with versus without corticosteroids ( 58.2% vs 18%, P <0.001) (Table 3).
The IQR time from symptom onset to SARS-CoV-2 RNA clearance was longer in corticosteroid treatment group compared with non-corticosteroid treatment group ( IQR: 24 days vs 17 days, P = 0.026) (Table 3).
As shown in Table 4, after IPW analysis, there were significant differences between corticosteroids and non-corticosteroid treatment for 28-day mortality, in-hospital mortality, acute liver injury, and SARS-CoV-2 RNA positive more than 20d.
Cumulative of overall 28-day survival curves for corticosteroid treatment group and non-corticosteroid treatment group were presented in Figure 3. The survival rate was significantly lower in the corticosteroid treatment group than in the corticosteroids free group (41/55, 74.54% vs 48/50, 96.0%, P = 0.014, log-rank test) (Figure 3A). After IPTW analysis, the cumulative of survival rate was still significantly different between two groups. (P = 0.014, log-rank test) (Figure 3B).
The difference in survival rates were consistent across subgroups based on gender, age, lymphocyte, D-dimer and albumin (Figure 4).
Risk factors for 28-day mortality in severe patients with COVID-19/HBV co-infection
In univariate analysis, age, lymphopenia, D-dimer greater than 1 μg/ml, albumin less than 30g/L on admission and corticosteroid treatment were associated with 28-day mortality of severe COVID-19 patients with HBV co-infection. Additionally, the multivariate Cox regression analysis revealed that D-dimer greater than 1 μg/ml on admission (OR, 10.686, 95%CI, 2.421–47.159, P=0.002) and corticosteroid treatment (OR, 11.236, 95%CI, 1.273–99.154, P=0.029) were independent risk factors for 28-day mortality of severe COVID-19 patients with HBV co-infection (Table 5).
Low lymphocytes, high leukocytes and high neutrophil counts, low albumin, high CRP levels, high LDH, and high D‑dimer levels were significantly associated with death (all P<0.05) (shown in supplementary material, Tables S1 and S2). By contrast, levels of ALT, AST, ALP, IL-6 and PCT were not associated with death (Table S2). The primary SOFA and APACHE II scores were significantly higher in the non-survivors compared with the survivors (Table S2).
Corticosteroid therapy among severe patients with COVID-19 and HBV co-infection
Most patients (48/55, 87.3%) received corticosteroid therapy more than 7 days after symptoms onset, including 15 non-survivor patients. All patients in corticosteroid treatment group received methylprednisolone. In subgroup analysis, methylprednisolone average dose was significantly higher in non-survivors (83 mg/day) than in survivors (40 mg/day) (Table 6).
General clinical characteristics of non-survival patients with COVID-19/HBV co-infection
General characteristics and cause of death of 18 non-survival patients with COVID-19/HBV co-infection were listed in Table S3. Patients from No.1 to 16 received corticosteroid treatment and patient No. 17, 18 did not. Twelve patients ware male. Age ranged from 46 years old to 83 years old. 15 patients with corticosteroid treatment had very high D-dimer level. In these patients, most causes of death were severe ARDS and organ failure, including of live, heart and kidney (Table S3).