key: cord-1026038-60yka189
authors: Nakamura, Hideta; Miyagi, Kazuya; Otsuki, Mariko; Higure, Yuuri; Nishiyama, Naoya; Kinjo, Takeshi; Nakamatsu, Masashi; Haranaga, Shusaku; Tateyama, Masao; Fujita, Jiro
title: Use of the interleukin 6 inhibitor tocilizumab in Japanese patients with cytokine release syndrome caused by COVID-19-related acute respiratory distress syndrome: A case series
date: 2020-10-07
journal: Respir Investig
DOI: 10.1016/j.resinv.2020.09.006
sha: cfc2b45073fe14230ecf69396f55564039c7bad2
doc_id: 1026038
cord_uid: 60yka189

nan

Coronavirus disease , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can induce acute respiratory distress syndrome and multiorgan failure [1] . Excessive production of proinflammatory cytokines has been observed in patients with COVID-19, and interleukin 6 (IL-6)-driven cytokine release syndrome (CRS) is considered to play a vital role in the development of COVID-19 [1] .

Blocking the IL-6 signaling pathway has recently drawn attention as a potential method to reduce COVID-19-related CRS [2] . However, it is controversial whether corticosteroids, administered as anti-inflammatory treatment, can ameliorate COVID-19-related CRS [3] .

Here, we have described the clinical course of seven patients with laboratory-confirmed COVID-19 who were treated with tocilizumab (TCZ), a humanized anti-human IL-6 receptor antibody. Although the study data are preliminary, they suggest the efficacy of TCZ in the treatment of COVID-19-related CRS in Japanese patients with COVID-19.

We conducted a case series of all adult patients with confirmed severe COVID-19 treated with TCZ (off-label use) at University of Ryukyus Hospital between March and May 2020.

The inclusion criteria were generated based on protocols from previous studies [4, 5] .

Patients were administered a single dose of intravenous TCZ (8 mg/kg), up to two additional doses were allowed. The primary endpoint was improvement in the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO 2 /FiO 2 ) and the values of the following The patients were predominantly male (6/7), and the median patient age was 70 years (interquartile range [IQR] 63-77 years). The median time from symptom onset to diagnosis was 9 days (IQR 4-9 days). Although all patients received favipiravir, nafamostat, and azithromycin before TCZ, no clinical improvement was seen.

Fever was observed in all patients. Only four (57.1%) patients with hypoxia presented with dyspnea; the median time to progress to dyspnea from the onset of COVID-19 was 5 days (IQR 2-8 days). All patients required oxygen therapy, including nasal cannula in two (28.6%), mask oxygen in two (28.6%), and high-flow oxygen therapy in three (42.8%). The three patients who received high-flow oxygen therapy eventually required invasive ventilation owing to severe acute respiratory failure; two patients received TCZ after J o u r n a l P r e -p r o o f intubation, whereas one patient received TCZ 2 days before intubation.

All patients showed lymphopenia (median 14.7%; IQR 6.4%-21.4%) and elevated CRP (median 15.26 mg/dL; IQR 11.77-20.68 mg/dL), ferritin (1005 ng/mL, IQR 562.1-1877 ng/mL), and IL-6 (median 108 pg/mL; IQR 33.1-160 pg/mL) levels. Four (57.1%) patients presented abnormal D-dimer levels (median 1.6 μg/mL; IQR 0.3-23.7 μg/mL). However, the patient developed catheter-related sepsis shortly after timely improvement of oxygen levels and died on day 33 due to a sudden onset of severe bradycardia.

After TCZ administration, lymphocyte counts, which stayed at similar levels through day 3, showed a steady increase from days 7 to 14 ( Figure 1 ). CRP levels had decreased sharply at day 3, but by day 7, CRP levels returned to normal in all patients and remained normal at day 14. IL-6 levels in six patients significantly increased on day 3, followed by a consistent decline. Similarly, TNF-α levels showed a downward trend after a sharp increase on day 3.

Consolidation of the fibrotic change with ground-glass opacity was observed on computed tomography (CT) scan around day 7 in four severe cases. The three patients who underwent invasive ventilation showed bilateral diffuse lung infiltration on chest radiography, but the abnormal findings gradually resolved once gas exchange improved, except in the patient who died. Among the survivors, the median hospitalization duration in five patients was 27 days. The remaining patient was hospitalized for >8 weeks for poststroke care.

Infusion-related reactions (n = 1), hypertriglyceridemia (n = 1), and bacteremia (n = 1) were adverse events of TCZ administration.

This case series evaluated the clinical efficacy and safety of TCZ in seven patients with severe COVID-19. Rapid improvement of clinical symptoms, recuperation from hypoxia, and marked changes in proinflammatory markers were observed. An increase in IL-6 levels after TCZ administration reflected the inhibition of IL-6 binding to the IL-6 receptor [4] . Although randomized control trials are warranted to validate the efficacy of TCZ, our data support previous preliminary studies on TCZ treatment for COVID-19 [4] [5] [6] . Nevertheless, the benefit of TCZ might be small for critically ill patients.

In this study, marked improvement in hypoxia after treatment with TCZ was not observed in three patients. These patients had lower PaO 2 /FiO 2 (median 90.7; IQR 81.4-155.4) than the other four patients (median 247.6; IQR 142.6-325). Further, they had higher IL-6 levels (median 63.8 pg/mL; IQR 30.63-202.9 pg/mL) than the other four patients (median 109 pg/mL; IQR 108-160 pg/mL). IL-6 signals through two main inflammatory pathways referred to as cis-signaling or trans-signaling [7] . While cis-signaling activates acquired and innate immunity, trans-signaling can result in the dysfunction of endothelial cells, leading to vascular permeability and coagulation disorders [7] . Once these inflammatory pathways have been amplified by excessive IL-6, terminating the cytokine cascade may be challenging. Indeed, IL-6 levels correlate with mortality [6] . Therefore, TCZ should be J o u r n a l P r e -p r o o f administrated of at an early stage.

This study has several limitations. Because the number of cases was small, it was difficult to measure and account for confounding variables. In addition, the data may not be generalizable to a larger population.

In conclusion, TCZ administration may ameliorate COVID-19-induced CRS.

Well-designed controlled trials are required to investigate the efficacy of TCZ and determine the parameters that physicians should monitor during treatment in view of safety.

The authors declare that there are no conflicts of interest.

J o u r n a l P r e -p r o o f 

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Why tocilizumab could be an effective treatment for severe COVID-19?

The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The perspectives of clinical immunologists from China

Effective treatment of severe COVID-19 patients with tocilizumab

Pirot prospective open, single-arm multicenter study on off-label use of tocilizumab in patients with severe COVID-19

Tocilizumab treatment in COVID-19: a single center experience

Cytokine release syndrome in severe COVID-19

Author's names: Hideta Nakamura, Kazuya Miyagi, Mariko Otsuki, Yuuri Higure, Naoya Nishiyama, Takeshi Kinjo, Masashi Nakamatsu, Shusaku Haranaga, Masao Tateyama, Jiro Fujita Manuscript Title: Use of the interleukin 6 inhibitor tocilizumab in Japanese patients with cytokine release syndrome caused by COVID-19-related acute respiratory distress syndrome: A case series All authors are required to disclose any COI within 3 calendar years preceding the current year, prior to the submission of any manuscript in the subject matter of which any company, entity, or organization has an interest.

No If Yes: List the name(s) of authors and commercial entity(ies) and use as much space as necessary This statement will be kept for 2 years after the publication of the manuscript.Date of Completion: 15/6/2020Corresponding author's Name: Hideta Nakamura J o u r n a l P r e -p r o o f