- Tocilizumab is clearly effective in Covid patients hospitalized for a hypoxemic form and with hyper-inflammatory syndrome.
Appeared in the JAMA Internal Medicine, 3 articles explore the interest of the use of tocilizumab in hypoxemic forms of Covid-19. Tocilizumab is a humanized monoclonal anti-interleukin 6 receptor (anti-IL-6R) antibody. It is commonly used in rheumatoid arthritis, Horton’s disease, and cytokine release syndrome after treatment with CAT cells.
Its use during the triggering of the cytokine storm and in prevention of going into intensive care has been proposed from several observational studies which have even suggested a late benefit on mortality.
Three very unequal studies
The 3 studies reported in JAMA Internal Medicine cover a large American observational study and 2 randomized studies, one Italian (n = 121) and one French (n = 131). The results are apparently discordant, but they concern very different populations.
The US STOP-COVID study is the largest observational study (n = 4,500). This type of study is subject to many biases, but the presence of the best specialists in observational studies among the authors gives some credibility to its results. The Italian and French studies do not concern the same patients.
The American STOP-COVID study differs from other observational studies by its size and by the care given to the adjustment of patients from the Study of the Treatment and Outcomes in Critically Ill Patients With COVID-19 (STOP-COVID ), because patients on tocilizumab are younger and have fewer comorbidities.
In Covid + patients in the first 2 days of their passage in intensive care and on a median follow-up of 27 days, those treated with tocilizumab have a reduced risk of death by 29% compared to those who did not receive tocilizumab ( HR, 0.71; 95% CI, 0.56-0.92). The estimated 30-day mortality rate is 27.5% (95% CI, 21.2% -33.8%) in patients on tocilizumab and 37.1% (95% CI, 35.5 % -38.7%) in patients not treated with tocilizumab (risk difference, 9.6%; 95% CI, 3.1% -16.0%).
Patients not severe enough in Italy
The Italian randomized study recruited Covid + hospital patients who needed oxygen via a nasal cannula but who had no indication for an ICU visit. It was stopped prematurely for futility, due to the lack of improvement in primary (respiratory) criteria.
The main problem with this study is that the study population does not correspond to the population that has a cytokine storm: the mean CRP is 10 mg / L and there were very few deaths (overall mortality of 2.4% at 30 days), a surprisingly low death rate for a study of patients hospitalized with so-called severe Covid-19. In addition, 14 of the 60 patients randomized to the usual treatment group eventually received tocilizumab due to a secondary clinical worsening.
A remarkable French essay
The French prospective randomized trial is undoubtedly the most interesting because it is a perfect example of the realization of a methodologically strict trial in a period of disorganization of hospitals by a pandemic disaster. CORIMUNO-19-TOCI-1 is a Bayesian randomized trial that recruited hospital patients with moderate or severe Covid-19 pneumonia, needing oxygen, but who did not require high flow oxygen through nasal cannula , non-invasive ventilation or mechanical ventilation (score of 5 on the World Health Organization clinical progression scale [OMS-CPS]). A population with an overall 28-day mortality rate of 11.5%, more representative of the hyper-inflammatory syndrome (mean CRP at 120 mg / L).
On day 14, 24% of patients in the tocilizumab group required non-invasive ventilation (NIV) or mechanical ventilation (MV) or died compared to 36% in the group without tocilizumab, a reduction in 42% (RR 0.58; 90% CrI, 0.33-1.00), reaching the predefined efficacy threshold. On day 28, 7 patients died in the tocilizumab group and 8 in the control group (NS). Serious adverse reactions occurred in 20 (32%) patients in the tocilizumab group vs. 29 (43%) in the control group (P = 0.21).
Reduced risk of aggravation
From these 3 studies, it emerges that tocilizumab is clearly effective in Covid + patients hospitalized for a hypoxemic form and with a hyper-inflammatory syndrome. It should be remembered that many very severe forms of Covid-19 in intensive care are hyperinflammatory immunological diseases similar to ARDS. In the French study, the patients are very representative of this “cytokine storm”, with very high CRP, ferritin and D-dimers. The reduction in the risk of going into intensive care justifies medically and economically the use of this molecule in this type of patient.
The lack of reduction in mortality at 28 days is normal in a patient population that is likely to remain in intensive care for up to 5 weeks, but the trial would be off to a good start for a reduction in mortality. If this reduction in mortality is confirmed in the next publication, it will be consistent with the results of the large American observational study. It seems that we can forget the Italian study which concerned only mild patients with minimal inflammatory syndrome (CRP at 10 mg / L).
Select patients well
In the hypoxemic forms of Covid-19, there is therefore a window of opportunity for intense anti-inflammatory treatment, with corticosteroids or anti-IL6R, which must be applied neither too early (increased risk of infection), nor too late (too pronounced pulmonary and systemic lesions) and especially only in patients with hyper-inflammatory syndrome.
The discussion should therefore focus on the definition of this hyper-inflammatory syndrome (what level of CRP? Fibrinogen? Ferritin? …), the time to treatment and on the corticosteroid strategy with or without tocilizumab. The French team is testing this association (CORIMUNI-Tocidex trial). Indeed, the discussion is further complicated by the publication in the New England Journal of Medicine from a randomized study in the United States which found no benefit.
This is a randomized double-blind study, therefore of greater validity, but the problem is that if the patients do have hypoxemia and a hyper-inflammatory syndrome (CRP at 110 mg / L), their rate of mortality is low (5.6% and 4.9%) with many obese people, a single dose of tocilizumab and their IL6 level is not very high compared to CRP (?).
There are still many gray areas, but we must thank the researchers of the CORIMUNO group for having demonstrated that it was possible to urgently launch and carry out a quality clinical trial in France during a period of “war”. What some said was impossible.
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