key: cord-320902-1hfxju5f
authors: Filocamo, Giovanni; Mangioni, Davide; Tagliabue, Paola; Aliberti, Stefano; Costantino, Giorgio; Minoia, Francesca; Bandera, Alessandra
title: Use of anakinra in severe COVID-19: a case report
date: 2020-05-11
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.05.026
sha: 
doc_id: 320902
cord_uid: 1hfxju5f

Abstract Coronavirus Disease 19 is a global healthcare emergency with high lethality rate. Relevant inflammatory cytokine storm is associated with severity of disease and IL1 inhibition is a cornerstone treatment for hyperinflammatory diseases. We present here the case of a patient with critical COVID-19 successfully treated with IL-1 receptor antagonist (anakinra).

In December 2019, severe acute respiratory syndrome (SARS) coronavirus 2 (SARS- was firstly discovered in Wuhan, China. Since then, Coronavirus Disease 19 (COVID-19) has risen to a global healthcare emergency, starting in late February 2020 in Northern Italy and rapidly becoming pandemic. The spectrum of symptomatic SARS-CoV-2 infection ranges from mild to critical. While the former accounts for 80% of cases, severe disease with acute respiratory distress syndrome (ARDS) and critical disease with respiratory failure and/or multiple organ dysfunction are diagnosed in 15-30% and 5% of COVID-19 patients, respectively (1). In the first month of COVID-19 outbreak in Northern Italy, intensive care unit (ICU) admission represented 12% of all COVID-19 patients and 16% of those hospitalized (2) . Overall, COVID-19 estimated case fatality rate ranges from 2.3% in China to 7.2% in Italy (3). However, in China's virus pandemic epicentre during the early stage of COVID-19 outbreak, the in-hospital overall lethality rate was higher (28%), and rose up to 62-97% in severely-ill patients requiring mechanical ventilation. (4) . As of March 25 2020, in Lombardy, Italy, 1591 patients were admitted in ICUs, of them, 405 (26%) had died in ICU, 256 (16%) had been discharged from the ICU, while 920 patients (58%) were still in the ICU The IL-1 receptor antagonist (anakinra) is a cornerstone treatment for hyperinflammatory conditions such as Still's disease, and has been shown to be highly effective in the treatment of cytokine storm syndromes, including macrophage activation syndrome and cytokine release syndrome (9).

Anakinra has a very safe profile and high dosages have been used even in patients with severe viral infection (EBV, H1N1 and Ebola) (10).

We present here the case of a patient with critical COVID-19 successfully treated with Anakinra.

On February 28 th , 2020 an otherwise healthy 50 year-old man was admitted to the local Hospital in Crema, Lombardy because of fever and dyspnea. Infection with SARS-CoV-2 was confirmed by RT-PCR on nasopharyngeal swab and chest computerized tomography scan showed bilateral ground glass opacities. The patient was put on non-invasive ventilation and antiviral therapy with lopinavir/ritonavir plus hydroxychloroquine was started. At day 3, his conditions worsened requiring ICU admission at our Hospital for invasive mechanical ventilation and hemodynamic support. On ICU admission, the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) was 160 on pressure control ventilation, with positive end expiratory pressure (PEEP) 12 and FiO2 50%. High levels of acute phase reactants and progressive liver cholestatic injury were observed (Table 1) . Hepatic involvement with liver enzymes higher more than five-folds their upper limits contraindicated treatment with remdesivir or tocilizumab. At day 10, considering the patient's critical conditions (PaO2/FiO2 85, volume control ventilation PEEP 14 FiO2 50%) and the hyperferritinemic inflammatory status with ferritin levels more than 3000 ng/ml, use of off-label anakinra was considered and started with the following dosage schedule: 200mg intravenously followed by 100 mg every 6 hours subcutaneously. Lopinavir/ritonavir and hydroxychloroquine were interrupted and no other immunosuppressive or immunomodulatory drug, including glucocorticoids or immunoglobulins, was started. In the next 72 hours, a sharp reduction of inflammatory markers and ferritin, an increase in lymphocyte count and a significant reduction of liver enzymes were ob- (Table 1 ). Respiratory parameters improved by day 13 (PaO2/FiO2 270, pressure control ventilation PEEP 10 FiO2 30%), followed by a favourable radiographic evolution. At day 18 the patient was discharged from the ICU.

In the following days, respiratory function progressively improved. On day 21, 4 days after ICU discharge, the patient became febrile with increase in C-reactive protein levels and no alteration in ferritin levels. Considering the persistent improvement in respiratory function and on suspicion of central venous catheter-related bacteremia, anakinra was stopped. Intravenous catheter was removed and empiric antibiotic treatment started with vancomycin plus piperacillin/tazobactam, modified 2 days later to cefazolin according to the identification of methicillin-sensitive Staphylococcus aureus in blood culture. A complete and prompt response to antibiotic treatment was observed with normalization of acute phase reactants. Patient was discharged from the hospital at day 29 in healthy conditions and normal oxygen saturation on room air.

To our knowledge, this is the first report of a critical case of COVID-19 effectively treated with anakinra.

Current management of COVID-19 is supportive, as respiratory failure from ARDS is the leading cause of mortality. Vaccines and approved targeted therapies for SARS-CoV-2 infection are still lacking and a multitude of compounds are now under investigation . The need to urgently identify an effective approach to manage COVID-19 led to the testing of existing antiviral drugs commonly used for other viral infections (i.e., interferon, ribavirin, and lopinavir-ritonavir), at present with controversial results (11) . Remdesevir is a promising novel nucleotide analogue with in vitro activity against SARS-CoV-2 and proved activity against SARS-CoV-1 and MERS-CoV both in vitro and in animal studies (12) .

Recently a cytokine storm resembling secondary haemophagocytic lymphohistiocytosis (sHLH) has been suggested to drive a later hyperinflammatory stage of COVID-19, with a decisive role in poor prognosis (13) . sHLH is a hyperinflammatory syndrome characterised by lifethreatening hypercytokinaemia leading to multiorgan failure. A cytokine profile resembling sHLH, characterized by increased levels of IL-2, IL-7, granulocyte-colony stimulating factor, INF-γ, CXCL10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and TNFα was described in severe COVID-19 (13) . Predictors of mortality from a retrospective, multicentre study of 190 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1435·3 mcg/L in non-survivors vs 503·2 mcg/L in survivors) and IL-6 levels (5), suggesting that higher mortality rates may be associated with a virally driven hyperinflammation.

The possible role of anti-cytokine treatment with IL-6 inhibitor (tocilizumab) in respiratory failure associated to COVID-19 has been recently proposed (14) . In inflammatory cytokine storms, IL-1 is a key effector and its role in promoting pro-inflammatory cytokines, including IL-6, is well known (15) . Indeed, IL-1 inhibitor anakinra has shown to be highly effective in the treatment of cytokine storm syndromes (15) and has already been proven safe in patients with sHLH associated to viral infections such as EBV, H1N1 and Ebola (10). Its short half-life makes it a widely drug to be use in clinical practice also in critically ill patients, in the eventuality of overcoming situations in which a prompt treatment interruption is required such as bacteraemia as described above.

This first report suggests that in the cytokine storm occurring during severe COVID-19, IL1 inhibition may represent a safe and promising strategy to reduce inflammation preventing multi-organ dysfunction and an appropriate tailored treatment strategy is crucial.

Further larger cohort observations are needed to confirm the possible association with positive clinical outcomes. To date, May the 5th 2020, 12 clinical trials on anakinra in COVID-19 patients are registered on ClinicalTrials.gov, 7 of them recruiting patients. These ongoing studies will provide key information on safety and efficacy of anakinra in the hyperinflammatory response to SARS-CoV-2.

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

Critical Care Utilization for the COVID-19 Outbreak in Lombardy, Italy: Early Experience and Forecast During an Emergency Response

Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region

Clinical characteristics of coronavirus disease 2019 in China

Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Effective Treatment of Severe COVID-19 Patients with Tocilizumab

Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases