The RECOVERY study recently published an article showing tocilizumab's efficacy in COVID-19. This is a multicentre, open-label, realistic experiment. There was a significant mortality improvement where many significant secondary endpoints also came out positive (e.g., reduced intubation rate, reduced requirement for dialysis).

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How do we evaluate this research with previous studies?

Tocilizumab monotherapy was found to be ineffective in early trials. Tocilizumab became more successful over time while more patients in the trials got steroids. Steroid use rose to 88 per cent in the most recent study (REMAP-CAP), and tocilizumab was shown to improve mortality.

Tocilizumab blocks only one cytokine, which may not be enough to keep a cytokine storm at bay. Since steroid impacts more inflammatory processes, it can be used alone to treat COVID. Nonetheless, it's conceivable that combining tocilizumab with 6 mg dexamethasone will boost overall efficacy.

Since this study was primarily undertaken after the publication of promising findings on dexamethasone, 82 per cent of patients in the RECOVERY trial received steroid. When given in combination with dexamethasone, tocilizumab reduced mortality by 6% but had little effect when given alone. The discrepancy (p=0.01) is statistically important.

This is consistent with previous reports that tocilizumab is only effective when used in conjunction with a steroid. Maybe most intriguing, it implies that the true impact size of tocilizumab in combination with dexamethasone is greater than that recorded in the key study data (e.g. the absolute mortality benefit of 6 per cent, rather than 4 per cent).

Who should be administered with Tocilizumab?

The RECOVERY study involved hypoxemic COVID patients hospitalised with a C-Reactive Protein (CRP) dose greater than 75 mg/L. Advantages were observed in all patient subgroups (figure above). Furthermore, there was no discrepancy in benefit when considering patients receiving tocilizumab during 2 days of hospitalisation versus >2 days after hospitalisation.

There are a few other elements of patient selection worth considering. Patients with active non-COVID infection were not permitted to participate. Tocilizumab was also not given in some cases because the managing physician assumed it was contraindicated. As a consequence, an extra layer of professional discretion is required (rather than administering tocilizumab to every single patient with COVID and hypoxemia).

It's also worth noting that some patients experience bacterial or fungal superinfection, which causes CRP to grow again after a few weeks in the hospital. Tocilizumab cannot help these patients.

What does this mean for COVID patients who need to be admitted early?

For COVID-19, we now have 2 treatments: steroid and tocilizumab. Dexamethasone can be used to treat hypoxemia (a room air concentration of less than 92 per cent). Tocilizumab is also available to those with a CRP >75 mg/L (roughly half of admitted patients, according to the ISARIC4C database!). Early implementation of these therapies can minimise mortality and prevent intubation (benefiting both the patient and the medical system as a whole, because ICU beds and ventilators are often in short supply).

The availability of promising option COVID therapy highlights the importance of detecting and admitting patients early in the process of the disease (using home pulse oximetry to diagnose early deterioration). This stresses the importance of precise oximetry assessment in patients with darker skin pigmentation, which can be achieved using arterial blood gas evaluation if pulse oximetry findings are questionable.

What happens if tocilizumab isn't available?

An irony of the pandemic treatment is that important medications are often used up right away. Tocilizumab isn't an exception. Tocilizumab is a costly monoclonal antibody that is only used in a few hospitals. Tocilizumab manufacturing can be difficult to scale up quickly, resulting in drug shortages. Ultimately, since tocilizumab is pricey, certain hospitals will be reluctant to use it. As a result, tocilizumab may not be a viable treatment option for the majority of COVID-infected patients around the world for a number of reasons.

Interestingly, tocilizumab may not be the only immunomodulator available:

1. JAK-1/2 inhibitors (especially baricitinib) inhibit IL-6 and other cytokines. While the use of steroid and baricitinib has not been prospectively studied, baricitinib has been reported to be efficient for COVID-19.
2. The steroid can inhibit IL-6 and CRP levels, though not as effectively as tocilizumab). Many other trials have found that relatively high steroid doses (e.g., dexamethasone 20 mg/day or methylprednisolone 125 mg/day) are safe and beneficial in ARDS and COVID.​
3. If tocilizumab fails to work, patients with COVID and systemic inflammation may benefit from either baricitinib or greater steroid doses. Unfortunately, these options actually have a weaker evidence base than tocilizumab, so they might not be the best choice.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.