key: cord-1054460-7ody8989 authors: Sarhan, Rania M; Madney, Yasmin M.; Abou Warda, Ahmed E.; Boshra, Marian S. title: Therapeutic efficacy, mechanical ventilation, length of hospital stay, and mortality rate in severe COVID‐19 patients treated with tocilizumab date: 2021-03-17 journal: Int J Clin Pract DOI: 10.1111/ijcp.14079 sha: caeab71488e932496a77e18b879efc5343deda3c doc_id: 1054460 cord_uid: 7ody8989 BACKGROUND: The treatment of severe cases of COVID‐19 disease remains a dilemma so far, because there is no approved therapy for it. This study aimed to estimate the therapeutic efficacy of tocilizumab and its role in reducing the need for mechanical ventilation, length of hospital stay, mortality rate for these cases. METHOD: The study included 25 adult patients with confirmed severe COVID‐19 infection. Treatment of all patients followed Egyptian Ministry of Health COVID‐19 protocol in addition to tocilizumab IV (400‐800 mg) as a single dose and then the dose was repeated after at least 12 hours and up to 24 hours from the previous dose. All laboratory and clinical parameters were assessed before and within 24 hours after tocilizumab administration. RESULTS: After receiving TCZ, all patients showed significantly lower median IL 6, LDH, CRP, ferritin , TLC at P < .001, and D‐Dimer at P = .223 than their baseline levels. Also, the number of patients who required mechanical ventilation decreased from 11 to 8. Only five patients died after TCZ treatment. A moderate correlation was found between therapeutic failure and death outcomes and mechanical ventilation need at baseline. The median days of hospitalisation (IQR) were 10 (6‐16). CONCLUSION: Tocilizumab treatment in patients with severe COVID‐19 is safe and has significant therapeutic effects and a significant role in the improvement of all laboratory parameters. Also TCZ plays a significant role in the reduction of the length of stay in hospital and ICU, need for mechanical ventilation, and mortality rate. WHAT’S KNOWN: IL‐6 plays the main role in the acute respiratory distress syndrome (ARDS) associated with severe COVID‐19 infection. Consequently, serum IL‐6 can be considered as an important target in therapeutic management of severe COVID‐19 patients. WHAT’S NEW: Prospective study, carried on 25 adult patients with confirmed severe COVID‐19 infection using tocilizumab, showed significant improvement in their case. Tocilizumab, as an IL‐6 inhibitor, not only lowered IL‐6 level put also showed a significant reduction on median LDH, CRP, ferritin , TLC at P < .001 and D‐Dimer at P = .223 than their baseline levels. Improvement of all laboratory parameters using TCZ was reflected in the reduction of the length of stay in hospital and ICU, need for mechanical ventilation and mortality rate. polymerase confirmed with chain reaction (PCR); (B) pulmonary involvement which was determined by oxygen saturation (Sa02) of < 92% when breathing ambient air, or respiratory rate (RR) > 30, or PaO 2 /FiO 2 ratio < 300. Patients received TCZ I.V according to their weights (weight > 40 to ≤ 65 kg: 400 mg as a single dose, weight > 65 and ≤ 90 kg: 600 mg as a single dose; and weight > 90 kg: 800 mg as a single dose; the dose was repeated in ≥ 12 to < 24 hours if patient's condition has not improved). The improvement in symptoms was the primary end-point, while the laboratory and respiratory parameters improvements were the secondary end-points. Pre and post-analysis of clinical response, safety outcomes and laboratory parameters which included D-dimer; C-reactive protein (CRP) values; ferritin; LDH, Absolute Lymphocyte count, TLC and IL-6 levels, were determined within 24hr after TCZ administration for all patients. Chest computed tomographic (CT) scans were carried out for COVID-19 patients and analysed ( Figure 1 ). All patients had chest radiology showing more than 50% lesion or progressive lesion. Descriptive analysis was performed where continuous variables were reported as median with interquartile range (IQR). A Wilcoxon • IL-6 plays the main role in the acute respiratory distress syndrome (ARDS) associated with severe COVID-19 infection. Consequently, serum IL-6 can be considered as an important target in therapeutic management of severe COVID-19 patients. • Prospective study, carried on 25 adult patients with confirmed severe COVID-19 infection using tocilizumab, showed significant improvement in their case. • Tocilizumab, as an IL-6 inhibitor, not only lowered IL-6 level put also showed a significant reduction on median LDH, CRP, ferritin , TLC at P < .001 and D-Dimer at p = .223 than their baseline levels. • Improvement of all laboratory parameters using TCZ was reflected in the reduction of the length of stay in hospital and ICU, need for mechanical ventilation and mortality rate. severity can also be defined on the basis of hypoxia (SpO 2 ≤ 93%), respiratory distress, or abnormal blood gas analysis (PaO 2 50 mmHg). 6 Currently, antiviral therapy such as hydroxychloroquine, remdesivir, ritonavir, and lopinavir are considered for severe COVID-19 treatment. Lately, steroids such as methylprednisolone have been considered as a standard of treatment. 7 Tocilizumab (TCZ) is a recombinant monoclonal antibody that antagonises the IL-6 receptor. The ability of TCZ to block inflammatory response mediated with IL-6-in severe COVID-19 patients, made it one of the potential treatments in severe cases. TCZ effect in severe COVID-19 patients has been evaluated in various studies and there was a marked laboratory and clinical improvement of these patients. [8] [9] [10] [11] TCZ is considered a type of biological disease-modifying antirheumatic drug. Consequently, it increases the risk of serious infections as it weakens the innate immunity. 12, 13 Several studies, carried on COVID-19 patients using TCZ, had different opinions about its adverse effects. One study reported that TCZ treatment did not cause any obvious adverse effects, 8 while another study reported worsened symptoms and severe infection in elderly patients treated with TCZ and attributed this effect to the increased risk of bacterial and viral infection because of the suppression of body immunity. 14 Until now, tocilizumab is not approved officially in the treatment of COVID-19. We conducted this study to evaluate the therapeutic effect of TCZ and its effect on clinical and laboratory parameters, the mortality rate, and the length of stay in hospital in patients with severe COVID-19. The study included 25 adult patients aged ≥18 years with confirmed severe COVID-19 infection between June 1, 2020, and June 30, 2020, from Teacher's Hospital, Cairo, Egypt. Egyptian Ministry of Health COVID-19 protocol is used as a guideline for triaging and therapeutic management of COVID-19 cases. COVID-19 diagnosis is confirmed by nasopharyngeal swab RT-PCR. Moderate and severe patients are admitted for hospitalization, while mild cases were advised for home care and isolation. Treatment plan Signed Ranks test was used to compare continuous data before and after TCZ administration. Categorical variables were compared using the McNemar test. Correlations between study findings (clinical parameters and outcomes) and baseline patient characteristics were identified with pairwise Kendall rank correlation coefficients. Significance was defined as P < .05. All tests were performed using SPSS v17.0 (SPSS, Chicago, USA). The study was carried out after approval from the Research Ethical Committee of the faculty of Pharmacy, Beni-Suef University with serial number (REC-H-PhBSU-20014). Informed written consent was taken from each study subject and they were informed that their participation is voluntary and they can withdraw from the study at any time. The study was performed according to the good clinical practices recommended by the Declaration of Helsinki and its amendments. (Table 1) During the period from 1st of June till 30 of July 2020, 25 patients (21 males), age 55 (46-76) were admitted to the hospital with confirmed COVID-19 diagnosis by nasopharyngeal swab testing using RT-PCR. Patients were categorised into severe cases (SaO 2 < 92%) according to local MOH protocol. No one showed acute cardiac injury or cardiac arrest at admission. Twelve (48%) patients showed fever (temperature > 38°C) on the day of therapy initiation. The clinical characteristics of patients at baseline were illustrated in Table 1 . Comorbidities were present in most patients and hypertension was the most common one (64%) followed by diabetes (48%) and ischemic heart disease (32%). All patients' comorbidities are illustrated in Table 1 . All patients showed pneumonic radiological findings (ground-glass opacities). Nineteen (76%) patients required intensive care unit (ICU) admission. After receiving TCZ, all patients showed improvement in symptoms and oxygen saturation. A comparison was set between laboratory findings before and after TCZ administration as showed in Table 2 Correlations between patient demographics and laboratory finding after TCZ administration were studied. The patient age showed a weak correlation with both TLC and LDH levels post-TCZ (r = 0.292 and 0.302, respectively at P < .05), while BMI was weakly correlated with ferritin level after receiving the drug (r = −0.410, P = .005). Also, weak correlations were found between patient comorbidities and F I G U R E 2 Laboratory results before and after administering tocilizumab (data expressed as mean and SEM, (*) the difference is significant at P < .001 Total leukocyte count(IQR), cells/µL 10 000 (5350-12850) 7.6 (5.8-10.6) <.001 Absolute Lymphocyte count, % 9 (5.5-15) 12 (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) .135 Mechanical ventilation, no. The number of patients who required mechanical ventilation, decreased 12 hours after receiving TCZ than before its use (8 (32%) In the present study, the effect of TCZ was prospectively observed in the treatment of 25 patients with severe COVID-19. The effects of TCZ on inflammatory markers were observed after a short time from starting TCZ treatment. TCZ not only observed as anti-IL-6 receptor antibody but also made a significant reduction in other inflammatory markers such as LDH, ferritin, D-Dimer and total leukocyte count. This was reflected in decreased number of patients who required mechanical ventilation after receiving TCZ. All patients with severe COVID-19 who included in the study showed rapid improvement in laboratory and respiratory parameters. This confirms the findings of the previous study that considered TCZ as a safe option for hospitalised adult patients with severe COVID-19 and confirmed its therapeutic benefit through laboratory and respiratory parameters improvement. 15 Unfortunately, the symptoms of patients with severe COVID-19 usually deteriorate rapidly and even end with respiratory failure. Consequently, the need for oxygen therapy and mechanical ventilation in these patients increases resulting in increasing admission in the ICU and mortality rate of 4.3 to 11% despite of using the recommended standard treatment. 16, 17 Also, a previous study reported a mortality rate of 60.5% in critical cases, 18 while another study, in Italy, reported a 26% ICU mortality rate in critically ill COVID-19 patients. 19 While in the present study the situation was found to be different as only five patients of the 25 ones were died representing about 20% of the studied patients and all of them needed mechanical ventilation and there was no correlation between the mortality rate and the comorbidities of these patients. This is a reasonable ratio compared with other treatments in critical cases. The present study showed a significant improvement in the level The number of patients who required mechanical ventilation decreased after using TCZ and the length of hospital stay was short as the median days of hospitalisation (IQR) was 10 (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) . This confirms that TCZ administration shortens the length of stay in hospital in severe COVID-19 patients. Also, TCZ reduces the length of stay in ICU in COVID-19 patients with ARDS and this will lead to reducing the risk of invasive mechanical ventilation and death in these patients. 11 The study did not include a control group in which patients could receive the treatment plan of the Egyptian Ministry of Health COVID-19 protocol without the addition of tocilizumab. Our findings indicate that the TCZ treatment of critically ill patients with severe COVID-19 and ARDS has significant therapeutic effects which have been reflected in an improvement in all laboratory parameters especially IL-6 and a reduction of the length of stay in hospital thus in mechanical ventilation and ICU. Also, treatment with TCZ seems to be safe and effective in reducing the mortality rate in severe COVID-19 patients. None. Data available on request from the authors. The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Cytokine storm intervention in the early stages of COVID-19 pneumonia The definition and risks of cytokine release syndrome in 11 COVID-19-affected critically Ill patients with pneumonia: analysis of disease characteristics Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. 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