key: cord-0777266-fybbnn46 authors: Franzetti, Marco; Pozzetti, Ugo; Carugati, Manuela; Pandolfo, Alessandro; Molteni, Chiara; Faccioli, Paolo; Castaldo, Gioacchino; Longoni, Ernesto; Ormas, Valentina; Iemoli, Enrico; Piconi, Stefania title: Interleukin-1 receptor antagonist anakinra in association with remdesivir in severe Coronavirus disease 2019: A case report date: 2020-05-16 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2020.05.050 sha: 4a459b10ba9b140c9c8e89891a97f42f8a9a10da doc_id: 777266 cord_uid: fybbnn46 Abstract We report the first successful treatment with the IL-1 receptor antagonist anakinra, in association with the most promising and available antiviral therapy, of a severe case of novel coronavirus disease 2019 (COVID-19). We describe the diagnosis, clinical course, and management of the case, including the respiratory failure at presentation, the progression to a scenario characterized by profound inflammatory dysregulation similar to that observed during macrophage activation syndrome, and the clinical improvement after treatment with the IL-1 receptor antagonist anakinra. This case highlights the high tolerability and the interesting immunomodulatory profile of the IL-1 receptor antagonist anakinra in the setting of severe COVID-19 associated with remdesivir therapy. Further studies are needed to confirm the safety and efficacy of this combination strategy in the treatment of this emerging infection. Since the first reports of cases from the Hubei Province of China at the end of 2019, more than 80,000 cases of novel coronavirus disease 2019 (COVID- 19) have been diagnosed in China and thousands of cases have been reported in all continents ]. Italy has been one of the most involved countries since the end of February 2020 [Livingston 2020 ]. The lung involvement and the clinical deterioration seen in severe cases have been associated with a substantial increase in the levels of pro-inflammatory cytokines and interleukins (IL-2, IL-6, IL-7, Il-10) and inflammatory markers (D-dimer, ferritin, and C-reactive protein), with pro-inflammatory cytokines levels proportional to the severity of lung disease [Lin 2020 , Wang 2020 ]. This clinical condition resembles the inflammatory derangement seen in other scenarios, such as sepsis-induced macrophage activation syndrome (MAS) [Huang 2020] or immune dysregulation characterized by low expression of human leukocyte antigen D related (HLA-DR) on CD14 monocytes [Lukaszewicz 2009 ]. Moreover, preliminary observations have shown favorable outcomes when the IL-6 receptor inhibitor tocilizumab was used to treat severe COVID-19 patients [Luo 2020 ]. However, long half-life of tocilizumab and its limited availability in the clinical arena promote the investigation of other therapeutic options. Among these, the recombinant interleukin-1 receptor antagonist anakinra may be beneficial in reducing the inflammatory storm observed in severe COVID-19 cases. Anakinra has been commonly used in the treatment of rheumatologic conditions, but previous studies report its efficacy in reducing mortality in septic subjects with MAS [Lopalco 2016 , Shakoory 2016 ]. Of note, no specific antiviral therapy has been approved by randomized clinical trials at the moment, even though some antiviral compounds may be associated with clinical improvement as reported by a recent preliminary report of a individuals receiving remdesivir on a compassionate-use basis [Grein 2020 ]. On March 10, 2020, a 57-year-old man presented to the emergency department of our hospital with a 5-day history of sore throat, cough, and fever (maximal body temperature of 39° C). The patient did not disclose any contact with COVID-19 patients. Apart a history of tobacco smoke and a Body Mass Index of 30.8 kg/m 2 , the patient was otherwise healthy. As shown in Table 1 , a body temperature of 38.5°C and oxygen saturation of 92% while breathing on Venturi mask were reported at presentation. Laboratory results revealed lymphopenia, a slight elevation of C-reactive protein (CRP) and troponin I, while the electrocardiogram and the echocardiogram performed did not show any abnormalities. A high-resolution computed tomography (HRCT) of the thorax revealed multiple patchy ground-glass opacities in subpleural regions bilaterally, with apical signs of emphysema ( Figure 1 ). A pharyngeal swab specimen was obtained and sent for detection of SARS-CoV-2 by real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) assay: this was reported back within 6 hours as positive. The patient was tested for other respiratory viruses by nucleic acid amplification test and for Legionella pneumophila and Streptococcus pneumoniae by urinary antigens, without any evidence of concurrent infection. The patient was admitted at an infectious diseases unit with health care workers following airborne and droplets precautions. An on off-label treatment with lopinavir/ritonavir (400/100 mg every 12 hours per os) and hydroxychloroquine (200 mg every 8 hours per os) was started. Azithromycin (500 mg every 24 hours per os) and ceftriaxone (2 g every 24 hours intravenously) were empirically associated to the ongoing treatment. Despite this, the respiratory status of the patient further deteriorated, with oxygen saturation values dropping to 89% while on reservoir. During this time ventilatory support was offered to the patient, who repeatedly refused both non-invasive and invasive ventilation. A psychiatric evaluation did not disclose any conditions impairing the decision-making ability of the patient and the ethical committee of the hospital accepted the patient's decision to refuse ventilatory support. On day 7 of hospitalization the patient's clinical condition appeared extremely critical: ratio of arterial oxygen partial pressure to fractional inspired oxygen (P/F) was 50. Fever, asthenia and anorexia worsened and an increase of inflammatory markers (CRP, D-dimer, and ferritin) was noted with a profound change in lipid distribution. Due to the evidence of inflammatory dysregulation and the unavailability of tocilizumab in our hospital, treatment with anakinra was introduced (100 mg every 6 hours subcutaneously for seven days). The patient was screened for HBV and Mycobacterium tuberculosis infection: tests turned out negative. In addition, lopinavir/ritonavir was discontinued and the investigational antiviral remdesivir was started as compassioned use (loading dose 200 mg, followed by 100 mg every 24 hours intravenously for seven days). Progressive normalization of the body temperature was observed, with persistently critical respiratory function. Because of a concern of hospital-acquired pneumonia, on day 10 ceftriaxone and azithromycin were discontinued and treatment with linezolid (600 mg every 12 hours intravenously) and piperacillin/tazobactam (4.5 g every 6 hours intravenously) was started. Blood and urine cultures performed on day 10 yielded negative results. In the following days, the patient became afebrile and inflammatory markers dropped. By day 16, a substantial improvement in the respiratory function of the patient was also noticed, with oxygen saturation levels of 92% while on Venturi mask. New HRCT scans showed a progressive reduction of the consolidative lesions previously noticed. Pharyngeal swab specimens for SARS-CoV-2 testing were collected on day 24 and were positive. On day 32 supplemental oxygen was discontinued, oxygen saturation of 93% while the patient was breathing ambient air and he was proposed for transition to subacute care. To the best of our knowledge, we report the first treatment with the IL-1 receptor antagonist anakinra and rendesivir of a severe COVID-19 case ]. IL-1 is the apical pro-inflammatory mediator, inducing both its own production and the synthesis of several secondary inflammatory mediators, such as IL-6 [Sonmez 2018]. Due to the possible role of IL-1/IL-6 axis blockade in conditions resembling MAS, the critical status of our patient, and the shortage of tocilizumab in our institution, we considered the administration of anakinra, in association with the most promising available antiviral agent and with adequate anti-thrombotic therapy [Shakoory 2016 , Tanaka 2019 . Indeed, another possible and even more frequent pathological mechanism seems to be immune dysregulation with a decrease in HLA-DR expression on CD14 monocytes and overproduction of tumor necrosis factor-α (TNF-α) and IL-6 [Giamarellos-Bourboulis 2020]. Although this process could not implicate the overexpression of IL-1, because it may not affect the expression of this interleukin [Giamarellos-Bourboulis 2020], the prompt resolution of fever, the reduction of inflammatory markers, and the improvement in the respiratory function observed in our patient are suggestive of a potential positive effect of anakinra. Nevertheless, the long-lasting positive detection of SARS-CoV-2 on pharyngeal swab specimens did not preclude the clinical recovery of the patients. As it was described in previous reports, this may suggest a long viral shedding, despite clinical improvement or resolution of symptoms [Yang 2020 ]. Moreover, even if no venous thromboembolism was detected at a chest CT angiogram with contrast performed at day 10 after admission, anti-thrombotic therapy was also added as shown in Table 1 , as this strategy was suggested by progressively available evidence, particularly in consideration of the increase of D-dimer levels [Tang 2020 ]. The main adverse effects associated with the use of anakinra are injection site reactions and severe infections [Cohen 2020 , Lopalco 2016 ]. In our experience no injection site reaction was identified and the elevation of procalcitonin reported on day 7 preceded the administration of anakinra. Moreover, the progression of the lung consolidation detected on day 10 could be expression of ongoing viral infection and inflammation. Nonetheless, the short half-life of anakinra allows a very rapid interruption of its immunomodulatory effect, differently from what is observed for long-acting agents, such as tocilizumab [Bhagat 2011 ]. The present report has several limitations. First, IL-1 and IL-6 levels were not evaluated during the hospital stay of the patient due to logistic limitations in an already overwhelmed health system. Second, quantitation of SARS-CoV-2 viral loads were not performed, due to similar constrains. Finally, we cannot make any causal inference regarding the clinical improvement of our patient and the use of anakinra, because of the observational design of this report. In conclusion, this report highlights the potential role of anakinra in the treatment of respiratory dysfunction in COVID-19 patients. Clinical trials are needed to assess safety and efficacy of this immunomodulatory agent. No funding source has to be acknowledged. A written consent was obtained by the patient for all off-label treatments that have been provided. The contribution of the ethical committee of the hospital was required for difficult clinical choices as reported. No conflict of interest has to be acknowledged. ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Day 20. Favorable radiographic evolution with reduction of parenchymal consolidation in the lower lobes. Day 30. Further reduction in extension of the areas of parenchymal consolidation. Ectasia of the vascular structures in interstitial fibrosis areas. 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 Coronavirus Disease 2019 (COVID-19) in Italy Hypothesis for potential pathogenesis of SARS-CoV-2 infection-a review of immune changes in patients with viral pneumonia Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Monocytic HLA-DR expression in intensive care patients: interest for prognosis and secondary infection prediction Tocilizumab treatment in COVID-19: a single center experience Safety profile of anakinra in the management of rheumatologic, metabolic and autoinflammatory disorders Interleukin-1 Receptor Blockade Is Associated With Reduced Mortality in Sepsis Patients With Features of Macrophage Activation Syndrome: Reanalysis of a Prior Phase III Trial Compassionate Use of Remdesivir for Patients with Severe Covid-19 How to reduce the likelihood of coronavirus-19 (CoV-19 or SARS-CoV-2) infection and lung inflammation mediated by IL-1 Anakinra treatment in macrophage activation syndrome: a single center experience and systemic review of literature High-density lipoprotein (HDL) particle size and concentration changes in septic shock patients Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure Persistent viral RNA positivity during recovery period of a patient with SARS-CoV-2 infection Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy 990145 Study Group. A multicentre, double blind, randomised, placebo-controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate Risk of adverse events including serious infections in rheumatoid arthritis patients treated with tocilizumab: a systematic literature review and metaanalysis of randomized controlled trials