In severe cases of COVID-19, the focus has been on the cytokine storm that characterises the infection from the outset. Many studies have conducted experiments to try to block the components of the cytokine cascade. It has been found, for example, that dexamethasone is useful in critically ill hospitalised patients. Two recently published studies have investigated the use of IL-6 receptor antagonists to try to stop the cytokine storm. The two studies gave conflicting results, so the effectiveness of this strategy is still unclear. Here is the editorial published in the New England Journal of Medicine (NEJM).
Viruses cannot replicate on their own. They need a host for almost all their replicative functions. Similarly, many viruses are unable to cause damage without the action of the host's immune system. For these reasons, two strategies are often effective in ameliorating disease: the use of antivirals, which block replication, and the use of anti-inflammatories, which can limit the damage induced by infection.
In COVID-19, the role of localised inflammation was evident from the start, because severe symptoms in many patients develop late, when the SARS-CoV-2 viral load is declining. Among the main candidates to mediate inflammation in COVID-19 was interleukin-6, a cytokine produced by macrophages that induces a pro-inflammatory response and is often elevated in COVID-19 patients. One of the reasons for the interest in interleukin-6 is that we already have approved drugs that block the cytokine or its receptor. Enthusiasm for this therapy was so high that interleukin-6 blockade was widely used in the US even before we had evidence of its efficacy. However, in the absence of potent antivirals to block SARS-CoV-2 replication, it was unclear whether this strategy was safe. Two studies published in the NEJM regarding the use of IL-6 seem to provide contradictory results.
In the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP), an adaptive clinical trial, approximately 800 patients requiring respiratory support only, haemodynamic support only, respiratory support and haemodynamic support were randomly assigned to the placebo group or to the group with administration of a single injection of an interleukin-6 receptor blocker, tocilizumab or sarilumab. The primary end-point was death in hospital and number of days without respiratory or haemodynamic support at day 21. The group taking an interleukin-6 receptor blocker had an in-hospital mortality of 27%, compared to 36% in the control group. Patients taking the receptor blocker had a median of 10-11 days without organ support, compared to 0 days for controls.
In the COVACTA study, a more traditional randomised controlled trial, 452 patients with COVID-19 (oxygen saturation ≤93%) were randomly assigned in a 2:1 ratio to take either a dose of tocilizumab or placebo. The primary end-point was clinical status at day 28, mortality was a secondary outcome. The group taking tocilizumab at day 28 had a median clinical status of 1 (discharged or ready for discharge), and the control group had a median clinical status of 2 (out of the ICU and no oxygen therapy in place). Mortality was 19.7% in the tocilizumab group and 19.4% in the control group.
The REMAP-CAP study, an open-label study, showed positive results. The COVACTA study, a double-blind, placebo-controlled study, showed no relevant outcomes. It is unclear whether the open-label nature of REMAP-CAP may have influenced the clinical management decision-making process.
These are the last of several studies evaluating the role of interleukin-6 inhibition. Most did not find an effect on mortality. However, a recent preprint of the RECOVERY study showed that, as in REMAP-CAP, treatment with tocilizumab resulted in lower mortality rates in groups with different disease severity.
How can we make sense of these discordant results? The differences between the studies include the enrolment criteria, the time at which anti-interleukin-6 therapy was started (with respect to both the time of infection and the severity of inflammation), the primary end-point and the baseline therapy. Not all inflammation may be the same: patients with severe disease at initial presentation may have a different pathogenesis from those in whom inflammatory disease develops later, suggesting that the timing of treatment initiation may be crucial in understanding responses. Perhaps the greatest variable, however, may be the periods in which trials were conducted. The baseline treatment of COVID-19 has changed and mortality appears to have decreased since the start of the epidemic. A particularly notable change has been that patients with severe disease, the therapeutic target in most of these trials, are now almost universally taking glucocorticoids, as these drugs have been shown in July 2020 to reduce mortality. In the COVACTA study, only a minority of patients were treated with glucocorticoids. Glucocorticoids were given less to the tocilizumab group (19.4%) than to the placebo group (28.5%). In contrast, 93% and 82% of all patients in REMAP-CAP and the RECOVERY study, respectively, were receiving baseline glucocorticoid therapy. Subgroup analysis in the RECOVERY study indicated that those taking glucocorticoids showed improved survival, suggesting a treatment interaction with interleukin-6 inhibition. Interleukin-6 blockade plus glucocorticoids, acting in different ways, may be additive or synergistic. Alternatively, the use of glucocorticoids may simply be a marker of other changes in treatment that have occurred during the course of the epidemic.
These points raise complex issues. Does the value of interleukin-6 inhibition depend on the timing of treatment, showing benefit only when close to an acute event of late inflammatory decompensation? We rely on clinical trials to endorse or reject possible interventions. But what if study results change as baseline therapies improve, a problem typical of platform trials, which must always include updated controls? For now, we are left with evidence of the benefit of interleukin-6 inhibitors, at least in some circumstances, but how best to use them remains unclear.
Rubin EJ, Longo DL, Baden LR. Interleukin-6 Receptor Inhibition in Covid-19 - Cooling the Inflammatory Soup. N Engl J Med. 2021 Feb 25. doi: 10.1056/NEJMe2103108. Epub ahead of print. PMID: 33631064.