Viruses cannot replicate on their own. Instead, they rely on the host for almost all of their replicative functions. Likewise, many viruses are unable to cause damage without the host’s immune system. Because of this, two strategies can often improve the disease – antivirals, which block replication, and anti-inflammatories, which can limit the damage induced by the infection. In the lung, this latter strategy is exemplified by the treatment of Pneumocystis jiroveci, in which treatment with glucocorticoids reduces the severity of the disease and the risk of death.1.2 However, as the blockage of inflammatory pathways increases the possibility of decreasing the host’s response and increasing the replication of the pathogen, antibiotics or antivirals are used simultaneously.
With coronavirus disease 2019 (Covid-19), the role of localized inflammation was evident at first, because severe symptoms developed in many patients late after infection, when the viral load of coronavirus 2 severe acute respiratory syndrome (SARS-CoV -2) was decreasing. One of the main candidates for mediating inflammation in Covid-19 has been interleukin-6, a cytokine produced by macrophages that induces a pro-inflammatory response and is usually elevated in patients with Covid-19. One of the attractions of interleukin-6 is that there are already approved agents that block the cytokine or its receptor. In fact, the enthusiasm for this therapy was so great that interleukin-6 blockade was being used widely in the United States before we had any evidence of its effectiveness. However, in the absence of potent antivirals to block replication of SARS-CoV-2, it was unclear whether this strategy was safe. The results of two tests now appear on the daily, with apparently contradictory results.
In the multifactorial adaptive platform trial for community-acquired pneumonia (REMAP-CAP),3 which had an adaptive design, approximately 800 patients in need of respiratory support or blood pressure, or both were randomly assigned to receive a placebo or a single injection of an interleukin-6 receptor blocker, tocilizumab or sarilumab. The primary endpoint was a composite of in-hospital death and days without respiratory support or blood pressure until the 21st. The group that received an interleukin-6 receptor blocker had a 27% in-hospital mortality, compared with 36% in the control group and those who received the receptor blocker had a median of 10 to 11 days without organ support, compared to 0 days for the controls. In COVACTA,4 a more traditional randomized controlled trial, 452 patients with Covid-19 (oxygen saturation, ≤93%) were randomly assigned in a 2: 1 ratio to receive a dose of tocilizumab or placebo. The primary end point was clinical status on day 28; mortality was a secondary result. The group that received tocilizumab had a median clinical status of 1 (discharge or ready to discharge), and the control group had a median clinical status of 2 (outside intensive care and did not receive supplemental oxygen). Mortality was 19.7% in the tocilizumab group and 19.4% in the control group. Both trials were open, which may have affected decision-making related to clinical management.
This is the latest of several studies that assess the role of interleukin-6 inhibition. Most found no effect on mortality.5-9 However, a recent preprint from the RECOVERY study showed that, as in REMAP-CAP, treatment with tocilizumab led to lower mortality rates in groups with different disease severities.10
How can we understand these disparate results? Differences between trials include enrollment criteria, the time when anti-interleukin-6 therapy was initiated (in relation to the time of infection and the severity of the inflammation), the primary outcome, and basic care. All inflammation may not be the same: patients with severe disease at the initial presentation may have a different pathogenesis from those in which the inflammatory disease develops later, which suggests that the timing of treatment may be crucial for understanding the responses. Perhaps the biggest variable, however, may be the time periods during which the tests were conducted. Baseline Covid-19 therapy has changed and mortality appears to have declined since the epidemic began. A particularly notable change was that patients with severe disease, the targets of therapy in most of these trials, now receive almost universally glucocorticoids, since these drugs were shown in July 2020 to reduce mortality.11 Only a minority of patients in the COVACTA study were treated with glucocorticoids. Less in the group that received tocilizumab (19.4%) than in the group that received placebo (28.5%) also received glucocorticoids. In contrast, 93% and 82% of all patients in REMAP-CAP and in the RECOVERY study, respectively, were receiving glucocorticoid therapy.10 Subgroup analysis in the RECOVERY study indicated that those who received glucocorticoids had a survival advantage,10 which suggests an interaction between treatment and interleukin-6 inhibition. Blocking interleukin-6 plus glucocorticoids, acting in different ways, can be additive or synergistic. Alternatively, the use of glucocorticoids may simply be a marker for other changes in treatment that have occurred during the course of the epidemic.
These points raise thorny questions. Does the value of interleukin-6 inhibition depend on the time of treatment, and is it beneficial only if close to an acute event of late inflammatory decompensation? We rely on clinical trials to endorse or reject possible interventions. But what if test results change as the underlying therapies improve, a particular problem with platform testing, which always needs to include contemporary controls? For now, we are left with evidence of the benefit of interleukin-6 inhibitors, at least in some circumstances, but the best way to use them is still unclear.