Coronavirus disease 2019 , caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), was declared a pandemic by the World Health Organization (WHO) on 11 March 2020. As at 24 May 2020 there have been 7135 cases of COVID-19 confirmed in Australia, of which 947 (13%) have been hospitalized, 202 (21%) required intensive care unit (ICU) admission and 102 have died. 1 Twenty percent of COVID-19 cases can develop acute respiratory distress syndrome (ARDS), which confers up to 62% mortality. 2, 3 Despite low rates of severe disease in Australia, 4 therapies for COVID-elated ARDS are urgently needed.
There is emerging evidence that COVID-19-related ARDS is triggered by excessive secretion of pro-inflammatory signaling molecules, termed cytokine release syndrome (CRS). 2 While there is no consensus definition of COVID-19 CRS, current data suggest it is clinically characterized by rapid-onset respiratory failure and biochemically characterized by raised interleukin-6 (IL-6) and its surrogate markers, including C-reactive protein (CRP) and ferritin. 5, 6 Tocilizumab, a humanized monoclonal antibody targeting the IL-6 receptor (IL-6R), was approved by the Therapeutic Goods Administration for the treatment of rheumatoid arthritis in Australia in 2009. 7 Established uses have since expanded to include juvenile idiopathic arthritis (JIA), giant cell arteritis, chimeric antigen receptor (CAR) T-cell therapy CRS and secondary hemophagocytic lymphohistiocytosis (sHLH) related to JIA, also termed macrophage activation syndrome. 8 Although tocilizumab is generally well tolerated in patients with rheumatic diseases, serious infections are reported at a rate of 4.7 events per 100 patient-years of use, including bacterial, viral and opportunistic infections, some of which have been fatal. 7 Tocilizumab is relatively contraindicated in patients with active infection. 7, 9 Some clinical and laboratory findings in COVID-19 CRS are similar to those found in sHLH and CRS induced by CAR T-cell therapy. 2, 10 However, it is not yet known whether IL-6, which is implicated as causative in the latter two conditions 2,11 plays a similar role in COVID-19 CRS. 8, 11 IL-6 is also raised in severe sepsis, 12 but data related to tocilizumab in sepsis are limited to in vitro and animal studies, and other immune interventions in sepsis using tumor necrosis factor alpha and interleukin-1 antagonists have not been associated with improved outcomes. 13, 14 Following the publication of two small, uncontrolled, retrospective case series from China, 15 there has been considerable interest in tocilizumab use in patients with COVID-19. 2,10,16 Two case control series reporting positive short-term outcomes have now been published in the peer-reviewed scientific literature, 17, 18 and two additional case control series have been published to the preprint server medRxiv but are yet to undergo peer review. 19, 20 We describe our experience using tocilizumab in patients with severe COVID-19 pneumonia. 21 had undergone endotracheal intubation and were mechanically ventilated due to type 1 respiratory failure. The other 2 patients had rapid, progressive type 1 respiratory failure but did not meet the Berlin ARDS definition as continuous positive airway pressure was not applied due to concern for aerosolization of SARS-CoV2. The decision to treat with tocilizumab was made by consensus between the involved intensive care, respiratory, infectious diseases and immunology specialists. Informed consent was obtained from the patient in two cases and from the next of kin in the three intubated patients.
Clinical information for each patient was obtained from a review of electronic and paper medical record systems, from which sequential organ failure assessment (SOFA) score 22 and H-score 23 were calculated where possible. Ethics approval was not required at two sites and was obtained at one site. All patients consented to publication.
The five patients were aged between 46 and 74 years and were followed for between 13 and 26 days after tocilizumab therapy; see Figure 1 . Table 1 describes patient demographics, past medical history and time-course of events prior to tocilizumab administration. All patients additionally received broad-spectrum antibiotics; four patients received corticosteroids; and two received both hydroxychloroquine and lopinavir/ritonavir (LPV/r). The time from tocilizumab administration to improvement in oxygenation, defined as a 25% fall in fraction of inspired oxygen (FiO2) required to maintain peripheral oxygen saturation (SpO2) greater than 92%, ranged from 7 hours to 4.6 days; Table 2 describes tocilizumab dose, additional medications administered, progress following treatment and adverse events. Table 3 and Figure 2 describe
acute respiratory distress syndrome, coronavirus, immunomodulation, interleukin-6, pneumonia, tocilizumab, viral clinical and laboratory results before and after tocilizumab treatment, and in Table S1 the Supplementary Appendix details further laboratory parameters.
A 53-year-old man with a history of hypertension presented to hospital with fever and rapid-onset type I respiratory failure due to COVID-19 pneumonia. At presentation, partial pressure of oxygen in arterial blood (PaO2) was 99 mm Hg while receiving FiO2 80% yielding PaO2 to FiO2 ratio (PF ratio) of 93 mm Hg. He underwent endotracheal intubation and was mechanically ventilated using the ARDSNet protocol 24 to manage adequate gas exchange and noradrenaline to maintain mean arterial blood pressure greater than 70 mm Hg. A total of 6 days LPV/r and hydroxychloroquine were administered commencing at day 2 of hospitalization. On day 3 of hospitalization, intravenous (IV) tocilizumab 400 mg and methylprednisolone 70 mg (1 mg/kg) were administered. Noradrenaline was ceased 6 hours after tocilizumab administration. Two days after tocilizumab therapy, ventilatory function improved, but signs of encephalopathy arose when sedation was weaned. Corticosteroids were therefore ceased and encephalopathy resolved rapidly.
Ventilator-associated pneumonia, diagnosed 3 days after tocilizumab administration, was treated with piperacillin/tazobactam. Three days following tocilizumab administration, the patient was extubated. He was discharged from ICU 5 days after tocilizumab administration, ceased oxygen therapy 1 day later, and was discharged home after a further 4 days.
A 74-year-old man with a history of type II diabetes and hypertension presented to hospital with COVID-19 pneumonia, with SpO2 95% on room air at presentation. He became hypoxic on admission day 3, and oxygen therapy, ceftriaxone and azithromycin were commenced. On day admission 9 he developed rapid-onset type I respiratory failure with clinical and biochemical features of COVID-19 CRS.
PaO2 was 119 mm Hg while receiving oxygen 8 L/min via Hudson mask (estimated FiO2 60%) yielding a PF ratio of 198 mm Hg. He was admitted to ICU and tocilizumab 800 mg IV was administered.
Following tocilizumab administration, estimated FiO2 requirement fell from 60% to 36% in 16 hours while maintaining SpO2 greater than 92%. He did not require endotracheal intubation. He was discharged from ICU 20 hours after tocilizumab administration. He then remained stable on FiO2 36% for 5 days, when oral prednisone 25 mg daily was commenced. Oxygen therapy was ceased 7 days after tocilizumab administration, and he was discharged home 6 days later. Corticosteroids were tapered to cessation over 2 weeks.
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A 46-year-old man with a history of obesity and asthma presented to hospital with COVID-19 pneumonia, with SpO2 95% on room air at presentation. He developed type I respiratory failure on admis- 
We present the first Australian cases of tocilizumab use in COVID- The dose and schedule of tocilizumab used in our series varied between patients, and there is treatment heterogeneity in the published literature. 15 If tocilizumab is shown to be effective for COVID-19 CRS, phase 2 dosing studies will be required. If global supply comes under strain, the needs of both COVID and non-COVID patients for tocilizumab will need to be considered.
In our series, the time from tocilizumab administration to an improvement in oxygenation, defined as a 25% fall in FiO2 requirement, ranged from 7 hours to 4.6 days, and radiographic improvement occurred at between 41 hours and 9.8 days. While no laboratory parameter reliably predicted clinical improvement in all five patients, changes in ferritin and lactate dehydrogenase generally correlated with clinical improvement, whereas D-dimer, creatine kinase, troponin-T and neutrophil counts did not. While all patients rapidly defervesced and CRP rapidly normalized, these are IL-6-dependent processes, 29 and so are unlikely to predict clinical improvement.
This series illustrates that tocilizumab can be associated with favorable clinical outcome in some cases of severe COVID-19 pneumonia. The Australian Society for Clinical Immunology and Allergy (ASCIA) recommends IL-6 blockade be considered early in critically ill patients with severe COVID-19 pneumonia. 9 We concur with these recommendations and advocate for collaborative, multidisciplinary management of such patients, including judicious use of tocilizumab, while awaiting the results of large multicenter placebo-controlled randomized trials.
The authors have no conflicts of interest to declare.
Ethics approval was obtained from the Monash Health Human Research Ethics Committee. All patients had an opportunity to review the manuscript and consented to their cases being published.
All authors had full access to all of the data in the study.
Timothy A. West https://orcid.org/0000-0002-5469-5501