Efficacy and safety of tocilizumab in COVID-19 patients

Demographics and clinical characteristics

Table 1 shows the clinical characteristics of 181 COVID-19 patients, including 92 treated with tocilizumab and 89 conventionally treated patients. The mean ages of the tocilizumab and conventionally treated patients were 68.8 (range, 25-87) and 66.8 (range, 25-85) years, respectively. Among those receiving tocilizumab, 65 (70.7%) had at least one coexisting disorder (i.e., hypertension, diabetes, cardiovascular and/or cerebrovascular disease, cancer, or liver cirrhosis), whereas only 25 (28.1%) conventionally treated patients had a coexisting disorder (P<0.0001). Among tocilizumab treated patients, 84.8% had critical or severe disease before tocilizumab, whereas only 46.1% of those receiving conventional treatment were critical or severe (P< 0.0001). Conventionally treated patients had significantly fewer hospitalization days than the tocilizumab group (mean, 16.4 vs. 27.5, P<0.0001). A total of 83 (90.2%) patients receiving tocilizumab and 88 (98.9%) conventionally treated patients were discharged from the hospital. Nine patients in the tocilizumab-treated patients died, whereas only 1 conventionally treated patient died. There were no significant differences in age, sex distribution, and negative-conversing days between the two groups.

Although fever, cough, shortness of breath, and fatigue were the initial symptoms of most patients, some patients developed chest distress, myalgia, and rhinorrhea. Atypical symptoms, such as diarrhea and headache, were less common and may have been associated with central nervous system [22] and digestive system invasion by SARS-CoV-2. After 1-3 days of tocilizumab treatment, a large portion of the COVID-19 patients showed clinical remission of their symptom (Table 2). We performed a logistic regression analysis to investigate whether COVID-19 severity and coexisting disorders of patients could affect the response to treatment. The results showed the critical patients were at a higher risk (OR=7.000, P=0.001) of showing no improvement in their cough than moderate and severe patients (Table 2). But it appears that the severity of the disease and coexisting diseases had no significant effect on other clinical symptoms.

Laboratory indices

Table 3 summarizes the laboratory indices of 181 patients. After tocilizumab treatment, white blood cell counts, C-reactive protein (CRP) levels, maximum temperature, minimum oxygen saturation, highest respiratory rate, and maximum heart rate were all significantly improved (P< 0.0001, P< 0.0001, P< 0.0001, P< 0.0001, P=0.0011, P< 0.0001, respectively), and the mean values were close to normal. Before treatment, CRP levels were higher in tocilizumab-treated than conventionally treated patients (50.8±67.3 mg/L vs. 23.0±28.7 mg/L) (Table 3). The mean IL-6 level before tocilizumab was 102.1±535.1 pg/mL, indicating that IL-6 was upregulated in these COVID-19 patients. Notably, after 1 week of tocilizumab treatment, IL-6 levels in these patients’ had increased to 369.7±778.6 pg/mL (P< 0.0001). In sharp contrast, the mean IL-6 level before conventional treatment was only 29.2±71.6 pg/mL.

Imaging features

All patients had abnormal chest CT on presentation before tocilizumab treatment. The primary abnormalities on the initial chest CT were plaque-like, ground-glass opacities and focal consolidation. However, after 1 week of tocilizumab treatment, most CT scans showed significant remission.

Clinical presentations

We evaluated the effects of tocilizumab treatment 1 week after treatment. We found that 72 patients showed improvement, 10 patients showed no improvement, and 9 critical patients had died. We also evaluated the effects of conventional treatment within 2 weeks of hospitalization. We found that 79 patients had improved, 9 patients showed no improvement, and 1 critical patient had died. In that patient, IL-6 level suddenly rose from 529.5 pg/mL to 5000 pg/mL before his death. This result suggests that in critical and severe patients, IL-6 levels may determine the prognosis and overall mortality of COVID-19 patients. We therefore focused our investigation on factors affecting early-stage clinical outcomes of severe patients.

Treatment

Immediately before and within 2 weeks after hospitalization, IL-6 levels in the 89 conventionally treated patients exhibited little change (mean, 29.2±71.6 pg/mL vs. 29.4±81 pg/mL, P=0.219). In sharp contrast, after 3 days of treatment, IL-6 levels in the 92 tocilizumab-treated patients had increased significantly (102.1±535.1 pg/mL vs. 337.7±723.8 pg/mL, P< 0.0001), while white blood cell counts had significantly decreased (7.6±3.7 ×10⁹/L vs. 6.6±5.7 ×10⁹/L, P< 0.0001). In addition, CRP levels were significantly lower 1 week after tocilizumab treatment (50.8±67.3 mg/L vs. 7.0±22.2 mg/L, P< 0.0001) (Table 3).

Three days after tocilizumab treatment, the body temperature of most patients had dropped, gradually moving closer to the normal range (Figure 1A). Simultaneously, the clinical symptoms were greatly attenuated over the following days. Figure 1B shows that 1 week after tocilizumab treatment, the CRP levels had decreased significantly in all but one patient. In that patient, who was critical, CRP levels greatly increased, and the patient died after 27 days in the hospital. Intriguingly, IL-6 levels increased significantly in tocilizumab-treated patients, though their condition was significantly improved (Figure 1C). No adverse drug reactions were reported during the tocilizumab treatment.

Figure 1. The values of maximum temperature, CRP, and IL-6 levels before and after tocilizumab treatment in COVID-19 patients. (A) The fever returned toward normal in most patients treated conventionally or with tocilizumab. (B) CRP levels decreased significantly after tocilizumab treatment and returned to normal in most conventionally treated patients. (C) IL-6 increased significantly after tocilizumab treatment in most patients.

Risk factors for poor clinical outcomes in critical COVID-19 patients

Univariate logistic regression analysis showed that high maximum temperature (OR=5.205 [95% CI, 1.160-23.358], P=0.031), maximum heart rate (OR=1.088 [95% CI, 1.010-1.171], P=0.026), and lactate dehydrogenase levels (OR=1.023 [95% CI, 1.004-1.043], P=0.018) were risk factors for poor clinical outcomes among critical patients before tocilizumab treatment. In addition, maximum heart rate (OR=1.169 [95% CI, 1.007-1.357], P=0.041), white blood cell count (OR=1.503 [95% CI, 1.029-2.196], P=0.035), mean platelet volume (OR=2.902 [95% CI, 1.040-8.100], P=0.042), blood urea nitrogen (OR=1.426 [95% CI, 1.048-1.941], P=0.024), sodium (OR=1.488 [95% CI, 1.027-2.158], P=0.036), and CRP (OR=1.082 [95% CI, 1.003-1.168], P=0.041) were all risk factors for poor clinical outcomes among critical patients 1 to 3 days after tocilizumab treatment. High minimum oxygen saturation (OR=0.704 [95% CI, 0.498-0.995], P=0.047) and high platelet count (OR=0.979 [95% CI, 0.958-0.999], P=0.042) were identified as protective factors against poor clinical outcomes among severe patients. Conversely, reduced platelet count was a risk factor for poor clinical outcomes (Table 4).

Study population

This single-center, retrospective observational study recruited 181 patients admitted to Huoshenshan Hospital (Wuhan, China) with confirmed COVID-19 between January 2020 and February 2020. Ninety-two patients were treated with tocilizumab, and 89 patients were treated with conventional treatment. All patients were diagnosed with COVID-19 based on World Health Organization interim guidance, and were clinically classified based on the Chinese management guidelines for COVID-19 (version 7.0) [32]. Moderate patients were defined as those with fever, respiratory symptoms and imaging evidence of pneumonia. Patients who met any of the following criteria were defined as severe: 1) tachypnoea (≤30 breaths/ min), 2) oxygen saturation ≤93% at rest, 3) PaO₂/FIO₂ <300 mmHg (1 mm Hg=0.133 kPa), and 4) progression of the lesion by >50% within 24-38 hours based on pulmonary imaging. Critical patients were defined as those with one or more of the following criteria: 1) respiratory failure, 2) septic shock, or 3) multiple organ dysfunction and/or failure.

According to the Chinese management guideline for COVID-19 (version 7.0) [32], the standard ages for patients who can be treated with tocilizumab are between 18 and 85 years. In addition, these patients must exhibit elevated IL-6 levels and multiple lung lesions showing significant progression of >50% within 24-38 hours on pulmonary imaging. The first dose of tocilizumab was 4-8 mg/kg. The recommended dose is 400 mg. A total of 100 ml of saline was added, and the infusion time was more than 1 hour. For patients presenting with fever, an additional dose (same dose as before) was administered if there was still fever after 24 hours. The interval between the two administrations was always ≥12 hours, and the cumulative number of doses was never more than 2. The maximum single dose never exceeded 800 mg.

Tocilizumab was contraindicated for pregnant or lactating women; patients with ALT/AST >5 times ULN, neutrophils <0.5×10⁹/L, platelets less than 50×10⁹/L; patients diagnosed of rheumatic immune-related disease; patients on long-term oral anti-rejection drugs or immunomodulatory drugs; patients hypersensitive to tocilizumab or any excipients; patients with active tuberculosis, hepatitis, and definite bacterial and fungal infections; organ transplant patients; and patients with mental disorders. IL-6 levels were measured using FACS or electrochemical luminescence methods (Roche Diagnostics GmbH). The normal range of IL-6 was <7 pg/mL.

The study was approved by Medical Research Ethics Committee of the Huoshenshan Hospital (Approval number: hssll033). All patients provided informed consent before treatment and agreed to publication of this case series. We are committed to protecting patient privacy and complying with the Helsinki Declaration.

Procedure

Demographic, clinical, laboratory, and treatment data were collected from electronic medical records. All data were checked by two physicians. The personal and clinical data collected included sex, age, medical history, and initial symptoms, including fever, cough, shortness of breath, fatigue, chest distress, myalgia, diarrhea, headache, and rhinorrhea. Real-time reverse transcriptase-polymerase chain reaction assays were used to detect SARS-CoV-2 infection. In addition, patients underwent an initial examination and then complete blood counts (white blood cells, neutrophils, lymphocytes, and platelets), serum biochemical tests (renal and liver function, carbon dioxide combining power, creatinine, and electrolytes), coagulation profile, procalcitonin, CRP, and myocardial enzymes 1-3 days and 1 week after tocilizumab. The patients’ follow-up endpoint was discharge or death. CT scans were used to image the lungs of all patients. The effect of treatment on COVID-19 patients after hospitalization for 1 week was evaluated based on Chinese management guidelines for COVID-19 (version 7.0) [32], as described previously.

Statistical analysis

Statistical analysis were performed using SPSS 19.0 (IBM, NY, USA) and R 3.5.1 software. Continuous variables are presented as the mean (range) or mean ± SD. If continuous variables conformed to a normal distribution, unpaired t-tests were used to analyze differences. Otherwise, the Mann-Whitney U test was used. When comparing datasets containing multiple groups, one-way analysis of variance was used for normally distributed datasets, and the Kruskal-Wallis test was used for datasets not normally distributed. Categorical variables were summarized as the counts and percentages, and analyzed using the χ² test or Fisher’s exact test, as appropriate. Univariate logistic regression analysis were performed to identify risk factors for disease progression. A two-sided values of P<0.05 were considered statistically significant.