key: cord-0816830-1bg1ykui authors: ElSeirafi, Mohamed MA.; Hasan, Hasan MSN.; Sridharan, Kannan; Zamoori, Alaa; Alkhawaja, Sana; Pasha, Sheikh Abdulla A. title: Efficacy and safety of tocilizumab in critically ill adults with COVID-19 infection in Bahrain: A report of 5 cases date: 2020-06-23 journal: Respir Med Case Rep DOI: 10.1016/j.rmcr.2020.101139 sha: 89ff87bd368c4a974fea7e1997076b9b27f13d25 doc_id: 816830 cord_uid: 1bg1ykui Tocilizumab has been recognized as one of the few existing biologic useful for combating COVID-19 infections especially in critically ill patient. We had experience in treating five critically ill patients with severe lung injury who were COVID-19 positive with tocilizumab. In the present case series, we have attempted to summarize their clinical profile, changes in laboratory biomarkers and outcomes. Tocilizumab has been recognized as one of the few existing biologic useful for combating COVID-19 infections especially in critically ill patient. We had experience in treating five critically ill patients with severe lung injury who were COVID-19 positive with tocilizumab. In the present case series, we have attempted to summarize their clinical profile, changes in laboratory biomarkers and outcomes. Tocilizumab is a monoclonal antibody to IL-6 receptor and is in widespread use for several auto-immune diseases particularly for rheumatoid arthritis. [1] Use of tocilizumab for treating critically ill adults with COVID-19 infections has been reported in limited numbers of patients. A recent systematic review that has included 10 studies has compiled data on just 29 patients. [2] No conclusion was drawn by the authors as the systematic review was observational without a comparator. However, a registry-based analysis of 21 patients revealed that tocilizumab administration did not influence ICU admission as well as mortality. [3] A retrospective study in 32 patients on tocilizumab therapy revealed no significant difference in the clinical outcomes compared to standard of care. [4] On the other hand, a single-center study from Italy revealed that out of the 43 critically ill patients treated in ICU, 32 (74%) recovered, weaned from the ventilator and were discharged to wards. [5] A vial of 400 mg tocilizumab costs around 2500 USD and not many developing nations can afford. Although several randomized clinical trials are ongoing with tocilizumab in the treatment of COVID-19infections, it is an arduous, time-consuming task with dissemination of results not expected very soon. Our center in Bahrain had experience in treating five patients with proven COVID-19 infection with tocilizumab and so we intend to summarize the characteristics of these patients in the present case series. A 95-year-old male with known history of diabetes mellitus, hypertension, dyslipidemia and benign prostatic hyperplasia was admitted with symptoms and signs suggestive of COVID-19 pneumonia. The patient was put on 5 L facemask with oxygen since admission with SpO 2 of 97%. His acute lung injury score was 2.5 and was classified as having acute respiratory distress syndrome (ARDS negative after 3 days and the patient was discharged from ICU. A 54-year-old man with known case of poorly controlled type 2 diabetes mellitus, had history of close contact with a COVID-19 positive patient and on screening with rt-PCR test, he was found to be negative for COVID-19. The patient was quarantined and after thirteen days, he presented with a 3-day history of drug cough and fever along with anosmia. On examination, he had tachypnea. Lung injury score revealed a severe lung injury. He had hypoxemia even with the facemask with 6L/min oxygen. Chest Xray revealed bilateral infiltrates and nasopharyngeal swab for COVID-19 was positive. The patient was initiated on oral hydroxychloroquine at 200 mg twice daily and injection ceftriaxone. As the patient required an increased requirement of oxygen therapy, piperacillin/tazobactam replaced ceftriaxone and two doses of plasma therapy was infused. As the patient did not show any signs of improvement, injection tocilizumab was administered at 400 mg for two doses. The patient improved significantly on the third day following tocilizumab injection and rt-PCR test for COVID-19 was negative on the fourth day. A repeat rt-PCR test was also negative after 6 days and the patient was discharged from ICU. A 64-year-old man with known case of bronchial asthma and morbid obesity (body mass index = 58.8 kg/m 2 ) with reduced glucose 6-phosphate dehydrogenase activity presented with a recent history of travel from Iran and had presenting complaints of dry cough, shortness of breath and fever. Physical examination revealed fine crackles at the bilateral lung bases and chest X-ray showed bilateral pulmonary infiltrates. His acute lung injury score was 2.5 and indicated ARDS. Nasopharyngeal swab for COVID-19 was positive and the patient was initiated on oral hydroxychloroquine 200 mg twice daily along with ceftriaxone, piperacillin/tazobactam, aizthromycin, ribavirin, pegylated interferon (received single dose) and plasma therapy (two doses). The patient did not show any signs of improvement but his oxygen requirement increased for maintaining appropriate oxygen saturation. The patient was shifted to ICU and was administered two doses of 400 mg tocilizumab infusion. Patient improved the following day with a negative COVID-19 test results twice on alternate days and the patient was discharge from ICU. A 37-year-old man without any significant past medical history presented with a 7-day history of fever along with 3-days duration of shortness of breath with productive cough for 1-day. On examination, the patient had crackles at the bilateral lung base and chest X-ray confirmed bilateral pulmonary infiltrates. Assessment of lung injury score revealed ARDS. Nasopharyngeal test for COVID-19 was positive. The patient received oral hydroxychloroquine 200 mg twice daily along with ceftriaxone, lopinavir/ritonavir, aizthromycin, ribavirin, pegylated interferon (received single dose) and plasma therapy (two doses). Patient did not show any signs of improvement and his oxygen requirement continued to increase and so two doses of tocilizumab 400 mg was administered. Following the second dose of tocilizumab, the patient showed marked signs of improvement and four days later he was found to be negative for COVID-19 test and a repeat test after two days was still negative. The patient was discharged from ICU. A 59-year-old man reported with shortness of breath and dry cough with fever. pneumonia. The nasopharyngeal test was positive for COVID-19. Chest X-ray revealed bilateral pulmonary infiltrates and lung injury score revealed ARDS. He was administered injections azithromycin, ceftriaxone, interferon, ribavirin and plasma therapy. As the patient's condition worsened, he was administered two doses of injection tocilizumab at 400 mg intravenously. The patient showed initial improvement followed by deterioration as his requirements for oxygen increased. One day following the second dose of tocilizumab injection, the nasopharyngeal test for COVID-19 was negative and a repeat test after two days confirmed the same. The patient also had positive blood culture (for Methicillin-resistant Staphylococcus aureus) with elevated procalcitonin and white blood cell count. The patient went into septic shock with multi-organ dysfunction. Despite active measures, the patient died on 16 th day of admission due to refractory hypoxemia and circulatory failure. All the five patients were initiated tocilizumab therapy following their raised serum interleukin-6 (IL-6) levels (> 50 pg/ml). The laboratory profiles of all the above patients with serum ferritin, C-reactive protein, procalcitonin, D-dimer, lactate dehydrogenase and interleukin 6 are shown in Table 1 . C-reactive protein decreases steadily in all patients except the one who died. All the patients except case number 5 showed a decline in total white blood cell (WBC) count and an increase in the lymphocyte count following tocilizumab therapy and none of the patients had abnormal liver function test. Interleukin-6 is a multi-functional cytokine that can promote the growth of T-cell population, activation and differentiation of B-cells and regulates the acute phase response in cases of systemic inflammation. [6] In critically ill COVID-19 patients with pneumonia, T-cells (GM-CSF + IFN-γ + ) and monocytes (CD14 + CD16 + ) with overexpression of IL-6 were identified in the biopsy specimen from their lungs. [7] Tocilizumab is an IgG1 humanized monoclonal antibody targeting IL-6 receptor and thereby has been theorized to play a significant role in severe critically ill COVID-19 patients. We observed in the present study that COVID-19 patients with severe lung injury responded dramatically following the introduction of tocilizumab. All our patients had serum IL-6 levels above 50 pg/ml. Until now, the only guidelines recommending tocilizumab therapy in COVID-19 patients is the National Health Commission of China. [8] The guideline recommend tocilizumab in patients with IL-6 levels above 20 pg/ml. The evidence on which this guideline was based is from 21 critically ill patients of which 20 improved and discharged within 2 weeks of tocilizumab therapy. We observed a similar recovery rate with tocilizumab. Of the five patients, four recovered and were discharged from ICU almost within a week. Only one died who had septicemia following secondary bacterial infection. Around 40% of patients with sepsis may have septic shock with a mortality risk of nearly 25%. [9] Only 3.7% of sepsis-associated mortality is preventable. [10] However, COVID-19 related sepsis has been reported in only 2-5% of the patients after 8-10 days. [11] Amongst those who improved with tocilizumab is a 95-year old man with several co-morbid diseases. Our patients also received other drugs such as ribavirin, hydroxychloroquine, azithromycin, lopinavir/ritonavir, pegylated interferon and plasma therapy as a part of the standard of care. The patients were receiving the standard of care for one or two days and since no significantly clinical improvement was observed or due to deterioration, they were initiated tocilizumab. We did not observe any specific laboratory-related adverse events following tocilizumab therapy. Although others [12] reported a trend of increased IL-6 immediately following tocilizumab followed by a decrease, we did not perform IL-6 analysis following tocilizumab administration due to cost constraints. However, all the patients had elevated baseline IL-6 levels. Further, except for one all others showed faster clinical improvement following initiation of tocilizumab that it was deemed unnecessary by the treating physicians. In addition, we could not compare our results with only patients who have received the standard of care. To conclude, tocilizumab appears promising in the treatment of critically ill adults with acute respiratory distress syndrome following COVID-19 infection. 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