Buonaguro et al.

J Transl Med (2020) 18:165

https://doi.org/10.1186/s12967-020-02333-9 Journal of
Translational Medicine

EDITORIAL Open Access

Anti‑IL6R role in treatment

of COVID‑19‑related ARDS
Franco Maria Buonaguro1, Igor Puzanov2 and Paolo Antonio Ascierto1*

Keywords:  COVID-19, SARS-CoV-2, ARDS, IL-6, Tocilizumab

The COVID-19 pandemic, which has exhausted the The paper published in this issue by Fu et  al., reports
momentum in China, is still in the exponential phase in preliminary data collected from 21 patients with SARS-
the rest of the world, without even reaching the peak. CoV-2- induced ARDS treated with tocilizumab [1].
What have we learned so far? What did Chinese scien- In this single arm study, patients with moderate to
tists and doctors teach us? severe COVID-19 disease received one or two doses of
SARS-CoV-2 infection is not like the seasonal flu. tocilizumab (400 mg/dose) in addition to standard thera-
While the range of symptoms for the two viruses is simi- pies used including lopinavir and methylprednisolone as
lar, the fraction with severe disease appears to be dif- reported in the Diagnosis and Treatment Protocol for
ferent. For COVID-19, data to date suggest that 80% of Novel Coronavirus Pneumonia (6th interim edition) [2].
infections are mild or asymptomatic, 15% are severe Most patients experienced clinical improvement includ-
infection, requiring oxygen and 5% are critical infections ing lower oxygen requirement (15/21, 75%), decrease of
characterized by acute respiratory distress syndrome CRP, increase in lymphocyte levels, decreased fever and
(ARDS), requiring mechanical ventilation. These frac- improved chest tightness. Two patients were taken off the
tions of severe and critical infection would be higher than ventilator within 5  days after the treatment with tocili-
what is observed for influenza infection. zumab, another one improved significantly [1].
There are currently no effective prophylactic or post- Based on this data, on March 3rd, 2020, National
exposure therapies. In patients infected with SARS- Health Commission of China included tocilizumab in its
CoV-2, it has been described that disease severity and 7th edition of COVID-19 therapy recommendations.
outcomes are related to the characteristics of the immune Limited experience in Italian centers obtained using
response. Interleukin (IL)-6 and other components of the tocilizumab for patients with moderate to severe COVID-
inflammatory cascade contribute to host defense against 19 revealed anecdotal evidence of time-correlated clinical
infections. However, exaggerated synthesis of IL-6 can improvements in oxygenation, decreased CRP, increased
lead to an acute severe systemic inflammatory response lymphocyte counts 24–48  h post administration, simi-
known as cytokine release syndrome (CRS). In the patho- lar to the Chinese experience. Better outcomes were
genesis of SARS-CoV-2 pneumonia, a study found that observed in non-intubated patients with elevated base-
a CRS involving a considerable release of proinflamma- line level of IL-6 CRP, ferritin and LDH.
tory cytokines occurred, including IL-6, IL-12, and tumor Thus, Italian Pharmaceutical Agency (AIFA) approved
necrosis factor α (TNF-α). a Phase II trial in 330 patients with COVID-19 induced
ARDS using tocilizumab started on March 19, 2020
(https​ : //www.aifa.gov.it/docum​ e nts/20142​ / 11279 ​ 0 1/
*Correspondence: [email protected]
1
Melanoma, Cancer Immunotherapy and Development Therapeutics
TOCIV​I D-19_Proto​col_v1.3_18Mar​zo202​0.pdf/68439​
Unit, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, Via Mariano 30d-9f31-185d-9812-29f02​ebebd​76) identified in USA as
Semmola, 80131 Naples, Italy NCT04317092. This is a multicenter, open label, single
Full list of author information is available at the end of the article

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Buonaguro et al. J Transl Med (2020) 18:165 Page 2 of 2

arm study with primary endpoint of overall mortality Availability of data and materials
All relevant data are included in the article.
1 month after registration. Secondary endpoints include
predictive/prognostic markers of baseline and on treat- Ethics approval and consent to participate
ment level of IL-6 and CRP, lymphocyte count changes, Not applicable.
radiological response, and other cytokine changes. Study Consent for publication
will include patients with SARS-CoV-2-induced intersti- Not applicable.
tial pneumonia, respiratory insufficiency (O2sat ≤ 93% or
Competing interest
PaO2/FiO2 ratio ≤ 300). Patients should be intubated less PAA has/had a consultant/advisory role for Bristol Myers-Squibb, Roche-
than 24  h before registration. In parallel, observational Genentech, Merck Sharp & Dohme, Array, Novartis, Merck Serono, Pierre
cohort with less stringent enrollment criteria will pro- Fabre, Incyte, NewLink Genetics, Genmab, Medimmune, AstraZeneca, Syndax,
SunPharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes,
ceed as well. Italfarmaco, Nektar, Boehringer-Ingelheim. He also received research funds
In the US, an adaptive Phase 2/3, randomized, double- from Bristol Myers-Squibb, Roche-Genentech, Array, and travel support from
blind, placebo-controlled study assessing efficacy and MSD.IP serves as consultant for AmgenFMB
safety of sarilumab (NCT04315298), another anti-IL-6R Author details
antibody started on March 16, 2020, sarilumab binds to 1
 Melanoma, Cancer Immunotherapy and Development Therapeutics Unit,
both membrane-bound and soluble forms of IL-6R. Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, Via Mariano Semmola,
80131 Naples, Italy. 2 Roswell Park Comprehensive Cancer Center, Buffalo, NY,
The clinical presentation of patients with severe forms USA.
of COVID-19 resembles cytokine release syndrome
(CRS) observed in some oncology patients treated with Received: 2 April 2020 Accepted: 8 April 2020
CAR-T cell therapies. There, IL-6R inhibition with toci-
lizumab (anti-IL-6R antibody) proved effective and was
FDA approved in 2017. IL-6 and its receptor signaling
were shown to play a role in immune response to H1N1 References
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FMB, IP, and PAA wrote and edited the editorial. All authors read and approved
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