COVID-19 pneumonia and the cytokine storm
So far, one of the main reasons for the high mortality rates of COVID-19 has been interstitial pneumonia with respiratory failure. Some evidence suggests that some of the respiratory symptoms are due to inflammation. And this inflammation is mediated by both immune cells like lymphocytes and/or macrophages and soluble factors like cytokines. So, when the immune response goes out of control, as seems to occur in some COVID-19 patients, the levels of pro-inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1 (IL-1) or tumor necrosis factor alpha (TNF-α) dramatically increase. This situation is known – from other fields – as a cytokine storm and is related to the severity and prognosis of the disease. The high amounts of pro-inflammatory signals attract many inflammatory cells into the lungs of patients with COVID-19, which may eventually lead to immune-related damage, lung functional affectation and mortality.
Using tocilizumab for COVID-19 pneumonia
Tocilizumab is a monoclonal antibody drug mainly used for the treatment of rheumatoid arthritis which selectively binds to soluble and membrane-bound IL-6 receptor, effectively blocking IL-6 signalling pathways and the subsequent immune responses.
Professor Cristina Mussini, University of Modena and Reggio Emilia, Italy : “At the beginning of the pandemic, clinicians had to look for innovative and creative solutions. Since the cytokine storm is mostly driven by IL-6, and even though the idea of inhibiting a single molecule might seem far-fetched, there are reports of some rheumatoid diseases where just acting on TNFα was enough to observe positive results, which supported the idea that tocilizumab could work.” – Read the full interview
Later, studies on COVID-19 patients in the intensive care unit (ICU) described increased plasma levels of cytokines including IL-6, IL-2, IL-7, IL-10 levels, and since those patients in the ICU are already suffering from either severe or critical respiratory affectation, using a drug that would decrease the effects of those circulating cytokines seemed like a good choice.
Reducing mechanical intubation is crucial
Most clinical studies on the use of tocilizumab in COVID-19 pneumonia focused on severe or critical patients, and the main outcomes evaluated were mortality and the need for mechanical intubation. In some of those studies, including EMPACTA and that by Guaraldi et al., treatment with tocilizumab led to both a decrease in mortality and in the need for mechanical intubation.
Professor Cristina Mussini explains why the latter is such an important measure: “Because it is directly linked to death. Some case series report up to an 80% death rate in mechanically ventilated COVID-19 patients. Basically, these patients are at increased risk not only from COVID-19, but also from mechanical ventilation-associated pneumonia or other ICU-related infections, and so mechanical ventilation is to be avoided as far as possible.” – Read the full interview
Central to tocilizumab’s effectiveness is timing and patient selection
Although, on the whole, most evidence seems to point towards the positive effects of tocilizumab for reducing mortality in COVID-19 patients, some trials failed to show benefits from the therapy. This may be related to various factors including patient selection, dosage, co-therapies, time of administration, etc.
This last variable seems to be key, for, as Dr Andrew Ip, John Theurer Cancer Center, USA explains: “tocilizumab is a drug that needs to be given in a very specific time window, or severity stage of COVID-19. When we use it in our cancer population, we only give it when patients meet certain criteria of severe inflammatory status – similarly, COVID-19 patients should be given a drug like tocilizumab when hyperinflammation, or overactive immune response, is causing patients to worsen, not because of active viral replication.” – Read the full interview
This factor is so important that a recent article in JAMA, which tested whether tocilizumab administration in early stages would avoid worsening of clinical status, found no differences to standard treatment.
What’s still needed for COVID-19 pneumonia treatment?
The obvious answer would be a vaccine and specific antiviral drugs, but until that becomes a reality, (sequential) drug combinations of tocilizumab with corticosteroids, antivirals and others have been proposed. However, one of the yet-to-be-answered questions posed by this disease is why some patients have such a bad disease progression, but not others, a point which strongly influences treatment decisions.
That is why Dr Juan Victor San-Martín López, Hospital Universitario de Fuenlabrada, Spain considers that: “Even more important than determining the dose, or whether one of those drugs is better than the other, or if a combination is possible, is to define who should receive them and when. In a disease with a clinical spectrum that varies between asymptomatic and severe respiratory distress with mechanical ventilation needs and > 50% mortality at this stage, finding early biomarkers for the cytokine storm to predict who is going to evolve for the worst would be key to intervening as soon as possible and avoiding treating those who do not need these drugs.” – Read the full interview