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We read with great interest the paper of Ramiro et al1 comparing the effectiveness of glucocorticoids (GC) treatment alone or in combination with tocilizumab in patients with COVID-19 versus supportive care. It provides relevant information about the immunomodulating approach to this novel disease, especially in a severe clinical scenario like the one caused by the cytokine storm syndrome. Throughout these months, it has been proven that many patients with moderate-severe COVID-19 develop a dysregulated immune response, characterised by a marked activation of the innate immunity, elevation of acute phase reactants and the release of proinflammatory cytokines such as IL-1 and IL-6, thus leading to a state of hyperinflammation.2 These findings have encouraged clinicians to use IL-blockers as off-label immunomodulators in patients who are refractory to standard-of-care treatment.
The anti-IL-1 receptor antagonist anakinra is highly effective in the treatment of syndromes involving cytokine storm, including the macrophage activation syndrome.3 4 Because its favourable safety profile, it has also been used in patients with severe viral infections or sepsis.5 6 Although the IL-6 blocker tocilizumab has been more frequently used in refractory COVID-19 in some countries, anakinra may be a better alternative for various reasons, namely, its disease-based rationale (targeting an upstream interleukin in the cytokine storm), rapid onset of action and safety profile: it can be adjusted or discontinued in infections or adverse events (AEs) thank to its short half-life of 4–6 hours, and it is suitable for the elderly, diabetics and patients with kidney or liver failure.
In most hospitals in Spain, tocilizumab has been widely used in refractory COVID-19, but GC were not included in the treatment protocols initially. Due to the above mentioned, along with the limited availability and high costs of tocilizumab, we decided to explore a therapeutic combination of a 3-day course of low-dose subcutaneous anakinra (LDSA; 100 mg/day) and GC in those patients with moderate-severe COVID-19 refractory to standard-of-care treatment. Our objective was quite ambitious, aiming to achieve a composite response goal that included radiological, clinical and analytical improvement within 72 hours. We selected nine patients with bilateral pneumonia, all of them needing oxygen supplementation, and with elevated laboratory parameters such as C reactive protein (CRP), ferritin or D-dimer at baseline. Six out of nine patients were previously treated with GC (methylprednisolone or prednisolone) before the administration of anakinra. After a 3-day course of LDSA treatment, six out of nine patients achieved the composite endpoint, and no radiological worsening was recorded in the remaining three patients. Median oxygen saturation (SpO2) at baseline was 92% with a significant improvement of 97% (p=0.007) at day 3 (D3). Significant differences were also observed in several of the laboratory parameters analysed between baseline and D3, with a decrease in median CRP (mg/L) (22.0 (IQR: 17.5–58.4) vs 9.0 (IQR: 3.1–18.4), p=0.01), median IL-6 (pg/mL) (45.5 (IQR: 19.2–82.4) vs 22.0 (IQR: 4.5–93.8), p=0.02), median fibrinogen (mg/dL) (501.0 (IQR: 482.0–668.0) vs 384.0 (IQR: 372.0–464.0), p=0.01), median D-dimer (ng/mL) (540.0 (IQR: 379.3–2415.0) vs 424.3 (IQR: 292.7–1114.1), p=0.02) and median neutrophils (×103/µL) (9.0 (IQR: 5.8–11.9) vs 6.4 (IQR: 4.0–8.7), p=0.03). An increase in median lymphocytes (×103/µL) was also noted (0.60 (IQR: 0.4–1.2) vs 0.9 (0.5–1.5), p=0.03) (figure 1). In addition, no serious AEs were observed, and no patient required admission to the intensive care unit or invasive mechanical ventilation in a short-term (72 hours) or medium-term (14 days) follow-up.
Our results show that anakinra may be a valid alternative option in the management of patients with moderate–severe COVID-19, constituting an available treatment with a lower cost than other immunosuppressants such as tocilizumab and a good safety profile. We decided on this short course of treatment, but anakinra allows different adjustments according to disease, age, comorbidities, and so different treatment courses7 could be established in advantage to tocilizumab, which is usually administered in a single dose. Other studies in COVID-19 have also reported good radiological and clinical outcomes in patients treated with anakinra at different doses and for a longer period.8–12 In our study, we did not follow a standardised course of GC as Ramiro et al but we consider that probably a strategy involving GC followed by LDSA or even LDSA alone (short LDSA courses have proven to be effective and non-inferior to prednisone for gout flares, in which there is also a great activation of innate immunity with marked acute inflammation)13 14 may be considered in the treatment of refractory COVID-19 as an alternative to other immunomodulators.
We would like to express our gratitude to Mr Thomas O’Boyle and the Spanish Society of Rheumatology (translation and proofreading service), Dr Carolina Marin (Rheumatology Department, Hospital Universitario Infanta Elena), the Vallecas COVID-Group, and the Pulmonology, Rheumatology and Clinical Laboratory Departments of the Hospital Universitario Infanta Leonor (especial thanks to Dr Tamar Talavan and Dr Belen Lopez-Muñiz).
Twitter @enriquecalvoA, @IrenCanamares, @lvaroMartnezAlc, @EscobarIsmael3
Contributors EC-A: Conceptualisation, methodology, formal analysis, investigation, resources, writing—original draft, review and editing, supervision, project administration. IC-O: data curation, writing—original draft, review and editing. MNN: methodology, formal analysis, investigation, data curation, writing—review and editing. AM-A: conceptualisation, methodology, formal analysis, software, writing—review and editing, investigation, resources, supervision, project administration. MdCOdlO: investigation, resources, writing—review and editing. IE-R: conceptualisation, methodology, formal analysis, investigation, writing—original draft, review and editing, FMS: investigation, resources, writing—review and editing.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests C-A reports personal fees from SOBI, personal fees (less than 10.000$ each) from NOVARTIS, personal fees from GEBRO PHARMA, personal fees from PFIZER, personal fees from ABBVIE, personal fees from LILLY, personal fees from GRUNENTHAL, personal fees from SANOFI, outside the submitted work.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Ethics approval All patients gave their informed consent. This prospective study is in accordance with the Helsinki Declaration and it was approved by the Ethics Committees of the Autonomous Community of Madrid and of the Spanish Agency of Medicines and Medical Devices (HIL-ANA-2020–07).
Provenance and peer review Not commissioned; internally peer reviewed.
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