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Effective treatment of severe COVID-19 patients with tocilizumab

Effective treatment of severe COVID-19 patients with tocilizumab


After analyzing the immune characteristics of patients withsevere coronavirus disease 2019 (COVID-19), we have identifiedthat pathogenic T cells and inflammatory monocytes with largeamount of interleukin 6 secreting may incite the inflammatorystorm, which may potentially be curbed through monoclonal an-tibody that targets the IL-6 pathways. Here, we aimed to assessthe efficacy of tocilizumab in severe patients with COVID-19 andseek a therapeutic strategy. The patients diagnosed as severe orcritical COVID-19 in The First Affiliated Hospital of University ofScience and Technology of China (Anhui Provincial Hospital) andAnhui Fuyang Second People’s Hospital were given tocilizumab inaddition to routine therapy between 5 and 14 February 2020. Thechanges of clinical manifestations, computerized tomography (CT)scan image, and laboratory examinations were retrospectively an-alyzed. Fever returned to normal on the first day, and other symp-toms improved remarkably within a few days. Within 5 d aftertocilizumab, 15 of the 20 patients (75.0%) had lowered their oxy-gen intake, and 1 patient needed no oxygen therapy. CT scansmanifested that the lung lesion opacity absorbed in 19 patients(90.5%). The percentage of lymphocytes in peripheral blood, whichdecreased in 85.0% of patients (17/20) before treatment (mean,15.52±8.89%), returned to normal in 52.6% of patients (10/19)on the fifth day after treatment. Abnormally elevated C-reactiveprotein decreased significantly in 84.2% of patients (16/19). No ob-vious adverse reactions were observed. All patients have been dis-charged on average 15.1 d after giving tocilizumab. Preliminary datashow that tocilizumab, which improved the clinical outcome imme-diately in severe and critical COVID-19 patients, is an effective treat-ment to reduce mortality.



Significance

In patients with coronavirus disease 2019, a large number of Tlymphocytes and mononuclear macrophages are activated,producing cytokines such as interleukin-6 (IL-6), which bind tothe IL-6 receptor on the target cells, causing the cytokine stormand severe inflammatory responses in lungs and other tissuesand organs. Tocilizumab, as a recombinant humanized anti-human IL-6 receptor monoclonal antibody, can bind to the IL-6receptor with high affinity, thus preventing IL-6 itself frombinding to its receptor, rendering it incapable of immune dam-age to target cells, and alleviating the inflammatory responses



Fig. 1.

Chest CT scans showed significant remission in both lungs in patients after the treatment with tocilizumab. (AC) Computerized tomography (CT) showed plaque-like and ground glass opacities before the treatment with tocilizumab. (DF) Chest CT showed diffuse infiltration in both lungs, but the lesions were clearly absorbed after the treatment with tocilizumab.






Fig. 2.

The values of CRP, body temperature, concentration of oxygen inhalation, and oxygen saturation before and after the treatment with tocilizumab for the 21 patients with COVID-19. (A) CRP decreased significantly after the treatment with tocilizumab and returned to normal in the majority of the patients. (B) The fever returned to normal in all 21 patients after tocilizumab. (C and D) Before the treatment, 20 patients needed oxygen therapy except 1 who refused. After tocilizumab, 15 patients had lowered their oxygen intake, and the oxygen saturation remained stable. Among them, one patient did not need further oxygen therapy on the third day. Therefore, the concentration of his oxygen inhalation during D3-D5 has marked as 21%, similar as oxygen content in normal air. (BD) *P < 0.05, **P < 0.01, ***P < 0.005, ****P < 0.0001. D, day after tocilizumab; SpO2, percutaneous blood oxygen saturation.






Conclusion In summary, tocilizumab effectively improve clinical symptoms and represses the deterioration of severe COVID-19 patients. Therefore, tocilizumab is an effective treatment in severe patients of COVID-19, which provided a therapeutic strategy for this fatal infectious disease.

Methods Patients. A total of 21 patients met the study conditions and were treated with tocilizumab between 5 and 14 February 2020. Seven of the patients were treated in The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), and 14 patients were treated in Anhui Fuyang Second People’s Hospital. All patients enrolled met the severe or critical criteria defined by the “Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (7th Interim Edition)” sponsored by the National Health Commission of the People’s Republic of China (22). For diagnosis, specimens were obtained by throat swabs under aseptic operation and tested with real-time RT-PCR assay that was developed from the publicly released virus sequence. The diagnosis of severity was defined if any of the following conditions were met: 1) respiratory rate ≥30 breaths per 1 min, 2) SpO2 ≤ 93% while breathing room air, 3) PaO2/FiO2 ≤ 300 mm Hg. A critical case was diagnosed if any of the following conditions were met: 1) respiratory failure, which requiring mechanical ventilation; 2) shock; 3) combined with other organ failure, need to be admitted to the ICU. Also, patients with active pulmonary tuberculosis combined with clear bacterial infection and fungal infection were excluded. The Medical Research Ethics Committee of the Anhui Provincial Hospital approved the study. All patients signed informed consent before using tocilizumab and agreed to publish this case series. We are committed to protecting patient privacy and complying with the Helsinki Declaration [approval no. 2020-XG(H)-015]. IL-6 Test. The value of IL-6 was measured by electrochemical luminescence method (Roche Diagnostics GmbH) in 18 patients or fluorescence-activated cell sorting analysis in 3 patients. Intracellular staining of IL-6 was performed without adding any restimulation. The cells were then collected, washed, and blocked according to the instructions of eBioscience. The normal range of IL-6 in peripheral blood is less than 7 pg/mL. Treatment and Observation. All patients received standard care as follows according to the “Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (7th Interim Edition)” (22): 1) antiviral therapy of lopinavir/ritonavir (200/50 mg per tablet for adults twice a day, two tablets each time, and the course of treatment does not exceed 10 d), IFN-α (5 million U each time for adults or equivalent dissolved in 2 mL of sterilized water and aerosol inhalation twice a day), and ribavirin (recommended for use with IFN or lopinavir/ritonavir, 500 mg per dose for adults, intravenous [i.v.] drip two to three times a day, and the course of treatment does not exceed 10 d); 2) glucocorticoid (use for a short period of time, range 3 to 5 d, as appropriate, at a dose not exceeding the equivalent of 1 to 2 mg/kg per day methylprednisolone for patients with rapid progress in respiratory function and imaging and excessive activation of the inflammatory response); 3) other symptom relievers and oxygen therapy. Also, they were treated with tocilizumab (Roche Pharma [Schweiz] Ltd; B2084B21).The first dose was 4–8 mg/kg body weight, and the recommended dose was 400 mg through an i.v. drip up to a maximum of 800 mg. Dilution was to 100 mL with 0.9% normal saline, and the infusion time was more than 1 h. In case of fever within 12 h, an additional dose was given (same as before), and the cumulative dose could not be more than two times. Clinical features including body temperature, concentration of oxygen inhalation, and oxygen saturations were recorded daily before and after treatment. A whole-blood white cell count was performed repeatedly. All patients had been spiral CT scanned on admission and a week later after the beginning of tocilizumab treatment using a 64-row spiral Optima CT680 scanner (GE Healthcare) in a whole-lung, low-dosage exposure, scanning with 5-mm slices. Data Collection. Clinical data were retrospectively analyzed by searching the information archived and coded by The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital) and Anhui Fuyang Second People’s Hospital, including gender, age, coexisting diseases, epidemiology, clinical symptoms, and peripheral oxygen saturations. Not all patients received relevant laboratory tests at a particular time, and we put emphasis on white blood cell count, lymphocytes percentage, CRP, and PCT. This study focused on the changes in body temperature, respiratory function, and CT findings before and after treatment with tocilizumab. Statistical Analysis. All statistical data were analyzed by IBM SPSS software v.16.0 and are expressed as means ± SD. Paired t tests analyses have been used in Fig. 2 BD. Data Sharing. Requests for materials should be addressed to the corresponding authors.

Acknowledgments This work was supported by Department of Science and Technology of Anhui Province and Health Commission of Anhui Province Grant 202004a07020001 and China National Center for Biotechnology Development 175 Grant 2020YFC0843800.



Xiaoling Xu, View ORCID ProfileMingfeng Han, Tiantian Li, Wei Sun, View ORCID ProfileDongsheng Wang, Binqing Fu, Yonggang Zhou, Xiaohu Zheng, View ORCID ProfileYun Yang, Xiuyong Li, Xiaohua Zhang, Aijun Pan, and Haiming Wei


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