key: cord-0764292-4nrj2x0b authors: Alattar, Rand; Ibrahim, Tawheeda B. H.; Shaar, Shahd H.; Abdalla, Shiema; Shukri, Kinda; Daghfal, Joanne N.; Khatib, Mohamed Y.; Aboukamar, Mohamed; Abukhattab, Mohamed; Alsoub, Hussam A.; Almaslamani, Muna A.; Omrani, Ali S. title: Tocilizumab for the treatment of severe coronavirus disease 2019 date: 2020-05-10 journal: J Med Virol DOI: 10.1002/jmv.25964 sha: 59231a3b62cd4d351a59dc9b837fb085a14d4029 doc_id: 764292 cord_uid: 4nrj2x0b Tocilizumab, an interleukin‐6 inhibitor, may ameliorate the inflammatory manifestations associated with severe coronavirus disease 2019 (COVID‐19) and thus improve clinical outcomes. This was a retrospective review of patients with laboratory‐confirmed severe COVID‐19 who received tocilizumab and completed 14 days of follow up. Twenty‐five patients were included, median age was 58 years (interquartile range, 50‐63) and the majority were males (92%). Co‐morbidities included diabetes mellitus (48%), chronic kidney disease (16%), and cardiovascular disease (12%). Fever (92%), cough (84%), and dyspnea (72%) were the commonest presenting symptoms. All patients received at least two concomitant investigational antiviral agents. Median oral temperature was on day 1, 3, and 7 was 38.0°C, 37.3°C (P = .043), and 37.0°C (P = .064), respectively. Corresponding median C‐reactive protein was 193 and 7.9 mg/L (P < .0001) and <6 mg/L (P = .0001). Radiological improvement was noted in 44% of patients by day 7% and 68% by day 14. Nine patients (36%) were discharged alive from intensive care unit and three (12%) died. The proportion of patients on invasive ventilation declined from (84%) at the time of tocilizumab initiation to 60% on day 7 (P = .031) and 28% on day 14 (P = .001). The majority (92%) of patients experienced at least one adverse event. However, it is not possible to ascertain which adverse events were directly related to tocilizumab therapy. In patients with severe COVID‐19, tocilizumab was associated with dramatic decline in inflammatory markers, radiological improvement and reduced ventilatory support requirements. Given the study's limitations, the results require assessment in adequately powered randomized controlled trials. globally, including nearly 140 thousand deaths. 5 Qatar reported the first COVID-19 case on 27 February 2020. 6 As of 17 April 2020, the total of laboratory-confirmed COVID-19 cases in Qatar was 4663 cases, including seven deaths. 7 In the majority of patients, SARS-CoV-2 causes a mild to moderate illness characterized by fever and respiratory symptoms, with or without evidence of pneumonia. 8 However, up to 10% of patients with COVID-19 may develop severe pneumonia with hypoxia, acute respiratory distress syndrome, and multiorgan failure. Such patients may require admission to an intensive care unit (ICU) for critical support and mechanical ventilation. 8, 9 Reported overall case fatality rates range from 0.9% in South Korea and 2.3 in China, to as high as 7.2% in Italy. 8, 10, 11 There are currently no approved therapeutic options for COVID-19 but a number of potentially useful antiviral agents are undergoing clinical evaluation. 12 COVID-19 is associated with increased plasma concentrations of proinflammatory cytokines. 9 Moreover, histopathological examination of lung tissue from deceased patients with COVID-19 showed evidence of extensive alveolar oedema, proteinaceous exudate and patchy inflammatory cellular infiltration. 13, 14 These findings suggest that severe SARS-CoV-2 infection is associated with a cytokine storm and pulmonary inflammation secondary to a dysregulated host immune response. 15 Tocilizumab is a humanized monoclonal inhibitor of the proinflammatory cytokine interleukin-6 (IL-6) and is licensed for use in the clinical management of cytokine release syndrome. 16 It has been postulated that tocilizumab may ameliorate the intense inflammatory manifestations associated with severe COVID-19 and thus improve clinical outcomes. 15 Peer-reviewed data on the clinical use of tocilizumab in severe COVID-19 are very limited. [17] [18] [19] [20] [21] We aimed to describe the clinical characteristics, laboratory findings and outcomes associated with the use of tocilizumab in patients with severe COVID-19 in Qatar. We retrospectively included all patients in Qatar with laboratoryconfirmed SARS-CoV-2 infection who received one or more doses of tocilizumab and completed at least 14 days of follow up. Laboratory findings are summarized in Table 2 . (Figure 1 and Figure 3 ). There was no statistically significant difference in the probability of being discharged alive from ICU between those who were on invasive ventilation at the time of initiation of tocilizumab (21, 84%) compared with those who were not (4, 16%) (log-rank P = .218). No baseline variables were independently associated with the primary outcome (Table 3) . Table 4 . We report the clinical characteristics and outcomes of 25 patients who received tocilizumab therapy for severe COVID-19. Unsurprisingly, all patients were in ICU at the time of tocilizumab initiation. Only three (12%) patients died during within 14 days of follow up. This is remarkably lower than all-cause mortality rates in critically ill COVID-19 cohorts reported elsewhere. 23, 24 However, the median age in this cohort was 58 years with a median Charlson co-morbidity score of one. Older age and increased co-morbidities have been consistently associated with poorer COVID-19 outcomes. 11, 25 It is likely that the lower mortality observed in this study is at least in part a result of those baseline characteristics. Similar to other reports of tocilizumab use in patients with COVID-19, the most striking clinical change observed in association with the tocilizumab in this study was the rapid decline in oral temperature and serum CRP levels ( Figure 2 ). [18] [19] [20] [21] This is a likely reflection of tocilizumab's immune modulating effect. The proportion of patients in this study who were on invasive ventilation decreased from 84% at the time of initiation of tocilizumab therapy to 60% at 7 days and 28% at day 14. The changes were statistically significant at both of these time points compared with the baseline status. Furthermore, there was a corresponding radiological improvement in 44% and 68% of patients at day 7 and 14, respectively. Notwithstanding the multitude of potential confounders in this study, it is not unreasonable to propose that this positive response may have been Tocilizumab is licensed for use in certain patients with chronic inflammatory conditions such as rheumatoid arthritis, giant cell arteritis and polyarticular juvenile idiopathic arthritis. 16 Amongst its well described adverse events are upper respiratory tract infections, headache, hypertension, and ALT rise. 26 The majority of patients in this report experienced adverse events. However, all patients were For example, anemia with ribavirin, QT prolongation with hydroxychloroquine. 26, 27 Importantly, tocilizumab may be associated with opportunist infections. 16, 26 One patient in this cohort experienced reactivation of oral Herpes Simplex infection and nearly one-third (8, 32%) had Candida species in their respiratory cultures. However, it is not possible to ascertain the extent to which the frequency, nature or severity of any of the adverse events observed in this study was related specifically to tocilizumab. Nevertheless, no scheduled tocilizumab therapy was discontinued as a result of concern over potentially related adverse events. In this study, patients received one to three doses of tocilizumab. Limitations of this study include its retrospective nature, lack of a control arm and potential confounding from concomitant application of multiple interventions. Moreover, determination of serum IL-6 levels before and after tocilizumab therapy would have been useful to demonstrate the immune modulating effect. 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