• Covid-19
• cytokines
• biological therapy

One of the very first publications showing promising results from the blockade of interleukin-6 signalling by the use of tocilizumab in patients with severe COVID-19 was that of Ramiro et al in July 2020, during the first wave of the pandemic.1 However, the results from further studies and randomised controlled trials regarding this issue hitherto remain inconclusive.2–7 To further support the work done by Ramiro et al (as well as those of other researchers), we would like to report the successful use of a single dose of intravenous 8 mg/kg tocilizumab in our department as a compassionate treatment in three consecutive patients during the second wave of the pandemic. These patients exhibited a rapid (within 24–72 hours) respiratory deterioration, despite already receiving the maximum indicated treatment. The administration of tocilizumab halted the further deterioration of these patients and prevented them from being intubated.

Patient 1, a middle-aged overweight man with medical history of arterial hypertension, presented to the emergency room (ER) on day 8 after initiation of COVID-19 symptoms, due to dyspnoea. He was tachypneic (respiratory ratio (RR)=25 breaths/min), while receiving 3 L/min of oxygen via a nasal cannula (arterial oxygen partial pressure (pO₂)/fraction of inspired oxygen (FiO₂)=216.6 mm Hg). His laboratory tests showed increased C reactive protein (CRP) (34.1 mg/L) and ferritin (960 ng/mL) levels. His chest X-Ray showed diffuse infiltrations (figure 1A). He was started on dexamethasone, ceftaroline and enoxaparin. Remdesivir was not available. During hospital day 1, his oxygen demands increased rapidly, and he was gradually placed on a 60% Venturi mask (VM) (15 L/min) with pO₂/FiO₂=178 mm Hg and RR=28 breaths/min. At that critical timepoint, he received tocilizumab. His condition stabilised and 4 days later, he was discharged, normopneic (RR=15 breaths/min), while breathing room air (pO₂/FiO₂=433.3 mm Hg). Patient 2, a middle-aged overweight woman with no medical history, presented to the ER on day 8 after initiation of COVID-19 symptoms and, due to dyspnoea, was already receiving azithromycin 500 mg/day. She was febrile and tachypneic (RR=22 breaths/min), with pO₂/FiO₂=511 mm Hg, while receiving 4 L/min of oxygen via a nasal cannula. Her laboratory values showed increased CRP (65 mg/L) and ferritin (705 ng/mL) levels. Her chest X-ray showed diffuse bilateral infiltrations. She was started on dexamethasone, ceftriaxone and enoxaparin. On hospital day 3, she became more tachypneic (RR=28 breaths/min), with increased CRP (245.7 mg/L) and ferritin (879 ng/mL) levels and lymphopenia (940 lymphocytes/μL). Ceftriaxone was replaced by remdesivir, piperacillin/tazobactam and vancomycin. Additionally, her pO₂/FiO₂ started dropping, so she was placed on progressively higher oxygen supply, reaching almost 100% via a closed 60% VM on hospital day 5 (pO₂/FiO₂=103.65 mm Hg, RR=30 breaths/min). Her chest CT showed extensive bronchopulmonary infiltrations bilaterally (figure 1B). At that critical timepoint, she received tocilizumab. Her condition stabilised, and on hospital day 14, she was discharged from the hospital normopneic with pO₂/FiO₂=227 mm Hg on 2 L/min oxygen. Patient 3, a man in his early 80s, with medical history of benign prostate hyperplasia and dyslipidaemia, presented to the ER on day 4 after initiation of COVID-19 symptoms, due to fever. His blood tests showed increased ferritin (877 ng/mL) levels. His chest X-ray exhibited slight infiltrations in both lung bases. He was febrile and had a pO₂/FiO₂ of 300 mm Hg while receiving 2 L/min of oxygen via a nasal cannula. He was started on ceftriaxone, azithromycin, enoxaparin, dexamethasone and remdesivir. After 4 days, he became tachypneic (RR=28–32 breaths/min) and started having progressively increased needs for oxygen supplementation. On hospital day 7, he was receiving almost 100% oxygen via a closed 60% VM with pO₂/FiO₂=108.33 mm Hg. His chest CT showed bilateral diffuse ground-glass infiltrations in the middle and lower lobes, mainly peripherally (figure 1C). At that critical timepoint, he received tocilizumab and he was placed on a non-rebreather mask. His condition stabilised and on hospital day 26 he got discharged normopneic while breathing room air (pO₂/FiO₂=290.5 mm Hg). Figure 1D–H shows the changes in different clinical and biochemical parameters before and after the administration of tocilizumab in all three patients.

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Figure 1

Three patients with severe COVID-19 requiring maximum levels of supplementary oxygen were successfully treated with a single dose of tocilizumab (RoACTEMRA). (A) Chest X-ray of patient 1 showing diffuse infiltrations especially on the left lower lobe. (B) Chest CT of patient 2 showing extensive bronchopulmonary infiltrations bilaterally. No pulmonary embolism was detected. (C) Chest CT of patient 3 showing bilateral diffuse ground-glass infiltrations in middle and lower lobes mainly peripherally. No pulmonary embolism was detected. (D) RR (breaths/min). (E) pO₂/FiO₂ ratio (mm Hg). (F) Levels of CRP (mg/L). (G) Levels of ferritin (ng/mL). (H) Lymphocytes/μL. *The arrows show the timepoint of each tocilizumab administration. Each colour matches with the same-coloured patient. CRP, C reactive protein; FiO₂, fractional inspired oxygen; pO₂, arterial oxygen partial pressure; RR, respiratory ratio.

Based on our expertise with the use of tocilizumab in autoimmune/inflammatory diseases, we believe that, supported by the observations of Ramiro et al, tocilizumab can be highly beneficial in severely ill patients with COVID-19, especially during this ‘gold window of opportunity’ right before mechanical ventilation is mandatory for their survival.