Viruses cannot repeat themselves. Instead, they rely on the host for almost all of their replicative functions. Similarly, many viruses cannot do harm without the host’s immune system. As a result, two strategies can often alleviate disease – antiviral drugs that block replication and anti-inflammatory drugs that can limit the damage caused by infection. In the lung, the latter strategy is illustrated by the treatment of Pneumocystis jiroveci, in which treatment with glucocorticoids reduces the severity of diseases and the risk of death.1.2 Because blocking inflammatory pathways increases the ability to reduce the host response and increase the replication of the pathogen, antibiotics or antiviral drugs are used concomitantly.
With coronavirus disease 2019 (Covid-19), the role of localized inflammation was clear early on, as severe symptoms developed in many patients after infection, when the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load decreased. . . One of the major candidates for mediating inflammation in Covid-19 was interleukin-6, a macrophage-produced cytokine that elicits a proinflammatory response and is often increased in patients with Covid-19. One of the drawbacks of interleukin-6 is that there are already approved drugs that block the cytokine or its receptor. In fact, the enthusiasm for this therapy was so high that interleukin-6 blockade was widely used in the United States before we had evidence of its effectiveness. However, in the absence of potent antiviral drugs to prevent SARS-CoV-2 replication, it was unclear whether this strategy was safe. The results of two trials now appear in the Magazine, with apparently conflicting results.
In the randomized, embedded, multifactorial adaptive platform trial for community-acquired pneumonia (REMAP-CAP),3 with an adaptive design, approximately 800 patients requiring respiratory or blood pressure support, or both were randomly assigned to placebo or a single injection of an interleukin-6 receptor blocker, tocilizumab, or sarilumab. The primary outcome was a combination of hospital deaths and days free of respiratory or blood pressure support until day 21. The group receiving an interleukin-6 receptor blocker had a 27% hospital mortality rate compared to 36 % in the control group and those receiving the receptor blocker had a median of 10 to 11 organ support free days compared to 0 days for 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 one dose of tocilizumab or placebo. The primary outcome was clinical status on day 28; death was a secondary outcome. The group receiving tocilizumab has a medical clinical status of 1 (discharged or ready for discharge), and the control group has a median clinical status of 2 (from intensive care and not supplemental oxygen). Mortality was 19.7% in the tocilizumab group and 19.4% in the control group. Both trials were open, which influenced the decision regarding clinical management.
This is the latest of several trials assessing the role of interleukin-6 inhibition. Most did not find an effect on deaths.5-9 However, a recent pre-print from the RECOVERY trial showed that treatment with tocilizumab, as in REMAP-CAP, resulted in lower mortality rates in groups with different severity of diseases.10
How can we make sense of these divergent results? The differences between the trials include the enrollment criteria, the time at which anti-interleukin-6 therapy was started (relative to the time of infection and the severity of inflammation), the primary outcome, and background care. All the inflammations may not be the same: patients with serious illnesses during the first presentation may have a different pathogenesis than those in whom inflammatory diseases develop later, suggesting that the timing of treatment may be crucial in understanding reactions. Perhaps the biggest variable, however, is the length of time the trials were conducted. The basic therapy of Covid-19 has changed and mortality seems to have declined since the beginning of the epidemic. A particularly striking change was that patients with serious illnesses, the targets for therapy in most of these trials, now receive almost universal glucocorticoids, as these drugs were shown in July 2020 to reduce mortality.11 Only a minority of patients in the COVACTA trial were treated with glucocorticoids. Less in the group receiving tocilizumab (19.4%) than in the group receiving placebo (28.5%) also received glucocorticoids. In contrast, 93% and 82% of all patients in REMAP-CAP and the RECOVERY study received glucocorticoid therapy, respectively.10 Subgroup analysis in the RECOVERY trial showed that those receiving glucocorticoids had a survival benefit,10 indicating a treatment interaction with interleukin-6 inhibition. Interleukin-6 blockade plus glucocorticoids, which act in different ways, can be additive or synergistic. Alternatively, the use of glucocorticoids may simply be an indication of other treatment changes that occurred during the epidemic.
These points raise thorny issues. Is the value of interleukin-6 inhibition dependent on the timing of treatment, and is it only beneficial if it is close to an acute late inflammatory decompensation? We rely on clinical trials to endorse or reject possible interventions. But what if the results of trials change as the underlying therapies improve, a specific problem with platform trials, which should always include contemporary controls? For now, we are sitting with evidence that we can benefit from interleukin-6 inhibitors, at least under some circumstances, but how to use them best remains unclear.