By Denise Baez
Use of tocilizumab and anakinra to treat coronavirus disease 2019 (COVID-19)-related cytokine storm yield mixed results, with early identification and treatment of cytokine storm before intubation being more important than which anti-inflammatory agent is used, according to a study published in the International Journal of Infectious Diseases.
“Prompt identification and treatment of COVID-19-related cytokine storm prior to intubation may be more important than the specific type of anti-inflammatory treatment,” reported Annette Langer-Gould, MD, Los Angeles Medical Center, Los Angeles, California, and colleagues. “Randomised controlled trials of targeted anti-cytokine treatments and corticosteroids should report duration of cytokine storm in addition to clinical severity at randomisation.”
Dr. Langer-Gould and colleagues described their initial experience with tocilizumab and anakinra for the treatment of patients with COVID-19-related cytokine storm at 15 Kaiser Permanente hospitals in southern California.
“While treatments were not randomly assigned, the evolution in practices over time provided an opportunity for us to compare the different approaches,” the authors wrote. “Our primary aim was to describe clinical outcomes among tocilizumab- or anakinra-treated patients with COVID-19, and to examine whether differences in outcomes could be accounted for by COVID-19-related cytokine storm severity and/or duration at the time of treatment initiation.”
The authors noted that treatment options for cytokine storm initially included tocilizumab without corticosteroids (no anakinra). However, clinicians at some Kaiser medical centres wanted to identify early cytokine storm through laboratory abnormalities in patients with increasing oxygen requirements and to initiate combined treatment with anakinra and corticosteroids. This was guided by prior institutional experience with treating macrophage activating syndrome and hemophagocytic lymphohistiocytosis, which present with similar but not identical manifestations of COVID-19-related cytokine storm.
Between March 1, 2020, and April 13, 2020, 52 patients received 1 to 4 doses of tocilizumab a median 14 days after symptom onset, and 41 patients received anakinra a median of 13 days after symptom onset, respectively. Most tocilizumab-treated patients received 1 dose (n = 26), 18 received 2 doses, 7 received 3 doses, and 1 patient received 4 doses. The median duration of anakinra treatment was 9 days and the median cumulative dose was 1,500 mg. All patients had bilateral infiltrates on chest x-ray or CT, and all non-intubated patients had increasing supplemental oxygen requirements at the time of treatment initiation.
Concomitant corticosteroids were used in only 7 tocilizumab-treated patients, although 12 others received rescue treatment with steroids later in their hospital course. In contrast, all anakinra-treated patients received concomitant corticosteroids. Of the patients treated with tocilizumab, 20 also received remdesivir, as did 16 patients in the anakinra group. Hydroxychloroquine was administered to 34 anakinra-treated patients and 48 tocilizumab-treated patients.
The risk of death was lower in the anakinra group (22.0%) than the tocilizumab group (46.2%). Among the 18 non-intubated patients at anakinra start, 14 never required intubation, 3 were subsequently intubated (1 extubated and 2 still intubated), and 1 elderly man was not intubated in accordance with his family’s wishes and died. Of the 23 intubated patients at anakinra initiation, 11 (47.8%) were extubated at last follow-up compared with 20 (40%) of the 50 intubated patients at tocilizumab initiation.
Those who died all had rising inflammatory markers consistent with worsening COVID-19- related cytokine storm at the time of death, and met COVID-19-related cytokine storm laboratory criteria longer (median, 3 days) compared with those extubated/never intubated (median, 1 day). Lymphopenia and/or neutrophilia resolved following treatment initiation in most patients who survived, but not in those who died.
After accounting for differences in disease severity at treatment initiation, this apparent superiority of anakinra over tocilizumab was no longer statistically significant (propensity score-adjusted hazards ratio = 0.46; 95% confidence interval, 0.18-1.20).
“In this study, we found that only 42.3% of tocilizumab-treated patients and 63.4% of those treated with anakinra responded favourably to treatment,” the authors wrote. “This disappointing tocilizumab experience led to a shift in practice to identify COVID-19-related cytokine storm earlier in the disease course, ideally prior to intubation, through a combination of laboratory abnormalities and respiratory deterioration. We accomplished this by empowering a team of experts in immunology to guide the ordering and interpreting of laboratory tests and the subsequent treatment of patients with cytokine storm with corticosteroids and anakinra. This approach resulted in better outcomes compared to the early tocilizumab-treated patients, but our analyses suggest that this could be due to earlier identification and treatment of COVID-19-related cytokine storm rather than superior efficacy of anakinra compared with tocilizumab. In addition, concomitant treatment with corticosteroids may have contributed to the better response observed in the anakinra-treated group.”
The authors noted that COVID-19-related cytokine storm appears to start 8 to 10 days after symptom onset and is characterised by high fevers, dyspnoea, hypoxemia, and bilateral pulmonary infiltrates, and can progress rapidly to acute respiratory distress syndrome and multisystem organ failure with or without hypercoagulability and, ultimately, death. They also noted that neutrophilia appears to be late finding in the COVID-19 cytokine storm, and along with acute kidney injury and hypotension, was more common at treatment initiation in the tocilizumab group. These factors were associated with a lack of response to both tocilizumab and anakinra.
The authors noted that the main limitation of the study is the possibility of unmeasured confounding that is present in all observational studies.
“Our most important finding is that COVID-19-cytokine storm lab abnormalities may be the earliest signal to alert clinicians to initiate corticosteroid treatment prior to respiratory failure,” the authors wrote. “Not measuring cytokine storm labs and delayed treatment, including with corticosteroids, may have contributed to worse outcomes in the tocilizumab-treated patients. Randomised controlled trials of targeted anti-cytokine treatments should report duration of elevated cytokine storm inflammatory markers in addition to clinical severity at randomisation.”