key: cord-297093-ld89vmct authors: Clark, Kristina E N; Collas, Oliver; Lachmann, Helen; Singh, Animesh; Buckley, Jim; Bhagani, Sanjay title: Safety of intravenous Anakinra in COVID-19 with evidence of hyperinflammation, a case series date: 2020-08-04 journal: Rheumatol Adv Pract DOI: 10.1093/rap/rkaa040 sha: doc_id: 297093 cord_uid: ld89vmct OBJECTIVES: Anakinra is a selective IL-1 inhibitor, which has been used in the context of secondary haemophagocytic lymphohistiocytosis. Although usually given in the subcutaneous form, previous anecdotal reports have emphasized its utility when given intravenously. Our aim is to report our experience on the beneficial effects of intravenous anakinra in patients with SARS-CoV-2 and evidence of hyperinflammation. METHODS: We report 4 patients with severe COVID-19 infection requiring intensive care admission and ventilatory support. RESULTS: All four patients showed evidence of deterioration with hyperferritinaemia, and increasing oxygen requirements, with supra-added bacterial infections. Upon commencement of intravenous anakinra, there was subsequent improvement in the patients clinically with reducing ventilatory support and inotropic support, and biochemically, with rapid improvement in inflammatory markers. CONCLUSION: Intravenous anakinra is safe to use in patients with COVID-19 and evidence of supra-added bacterial infection. Although its utility has not been confirmed in a randomized trial, current research in the COVID-19 pandemic aims to establish the utility of immunosuppression, including IL-1 blockade on the outcomes of patients with moderate to severe disease. Our case series support its use in patients with severe-life threatening COVID-19 and evidence of hyperinflammation. Anakinra is a recombinant IL-1 receptor antagonist originally marketed for use in rheumatoid arthritis. It has increasingly found off-label use in patients with haemophagocytic lymphohistiocytosis (HLH). Efficacy data predominantly comes from case series (1, 2) , where it achieves disease remission, normalization of laboratory abnormalities, and resolution of pyrexia from cytokine storm (3, 4) , even in the context of sepsis. Traditionally given subcutaneously, the intravenous form is safe at doses up to 10mg/kg (5) . Despite the limited evidence, consensus guidelines support its use in the treatment algorithm of cytokine storm (6) . COVID-19 typically presents with fever, dry cough and dyspnea, although the array of symptoms is wide. Mean time-lag from symptom onset to dyspnea is 5-8 days, and to acute respiratory distress syndrome (ARDS) is 8-14 days (7, 8) . ARDS affects 8-19% of patients (3) , and these patients have increased risk of cytokine storm and progressive multi-organ damage. Severe COVID-19 is more common in older patients, and those with certain comorbidities including obesity, diabetes and cardiovascular disease (9) . Severe COVID-19 is characterised by prominent alveolar damage, with focal reactive hyperplasia of pneumocytes, patchy inflammatory cellular infiltration as well as intravascular thrombosis. Key pathological cells include CD4+ and CD8+ T cells and macrophages. The cytokine profile is similar to HLH, with increased interleukin (IL)-6, IL-1β, IL-10, granulocyte macrophage -colony stimulating factor (GM-CSF), interferon-γ (IFN-γ) macrophage inflammatory protein 1-α, monocyte chemoattractant protein-1 (MCP-1), and tumour necrosis factor-α (3, 10, 11). SARS-CoV2 evades a number of immune system recognition points which usually initiate viralmediated immunity. The activation of innate immune cells by infected macrophages results in the expression of pro-inflammatory IL-1, IL-6 and TNF-α production through the NF-κB pathway. The concentrations of these cytokines continue to increase via a process of auto-amplification, and recruit adaptive immune cells (12) . Aberrant CD4+ T cell activation releases IFN-γ and GM-CSF. The GM-CSF results in increased CD14+ CD16+ inflammatory monocyte subsets, a subset rarely seen at significant levels in health (13) . This subset of monocytes express increased levels of IL-6 which are likely to be responsible for the acceleration and progression of a systemic ihinflammatory response. IL-1 and related pro-inflammatory pathways intertwined with aberrant T-cell responses play a crucial role in disease severity (14) . Elevated ferritin and IL-6 concentrations correlate with mortality (15) . We define hyperinflammation by this systemic inflammatory response, which has strong similarities to that seen in cytokine release syndrome. One current treatment strategy is controlling hyperinflammation with targeted immunosuppression. We describe a cohort of patients with severe SARS-CoV-2 infection admitted to the intensive care unit during the pandemic, with elevated ferritins between 4,000 -30,000 g/L. All four patients were diagnosed with COVID-19 and required ventilatory support. These patients all showed evidence of hyperinflammation with raised inflammatory markers, and CRP, and were given intravenous anakinra, with safe and successful use, suggesting the potential benefit from IL-1 blockade in this subgroup of patients with confirmed COVID-19. 30-year-old gentleman with a background of end stage renal failure (ESRF) secondary to birth asphyxia, and a DBD (donation after brainstem death) renal transplant (baseline creatinine 290 mol/L), maintained on sirolimus and tacrolimus. This was the patients' second transplant, the first being complicated by graft rejection, MAHA and requiring graft nephrectomy in 2013. The current transplant had taken place over a year prior to the current presentation, of which he had had one episode of BL nephropathy treated with steroids. He had been stable following this, with no significant infections. He presented with a 14-day history of feeling unwell with fevers, and a 5-day history of a cough, sore throat and difficulty breathing. Initial saturations were 80% on room air, which improved to 100% on 35% oxygen via a venturi face mask. His blood pressure (BP) was 127/73 mmHg, heart rate 95/min, temperature 38 o C, respiratory rate (RR) 21/min. Chest X-ray (CXR) showed bilateral patchy consolidation and nasopharyngeal swab (NPS) confirmed SARS-CoV-2. Blood tests revealed ferritin of 24617 g/L, creatinine 519 µmol/L, CRP 92mg/l. Oxygen was titrated to keep his saturations above 94%, and he was initiated on co-amoxiclav. After two days, with increasing oxygen requirements and progressive CXR consolidation, he was transferred to the ICU where he was commenced on CPAP (continuous positive airway pressure). The sirolimus was stopped but he remained on tacrolimus. Ferritin at the time was 23788 g/L, CRP 73mg/l, and procalcitonin 17.27 mcg/L (normal range <0.5mcg/L). Microscopy from blood cultures and urine cultures were all negative, and CMV and EBV viraemias remained very low level. Given the increasing oxygen requirement, and persistent inflammatory state, intravenous anakinra 200mg was initiated (Table 1) . A marked improvement in ferritin was seen within two days, CRP steadily decreased ( Figure 1 ), creatinine improved, and his respiratory effort stabilised. After 3 days of CPAP, he was weaned off, and stepped down to the ward. Intravenous anakinra was stopped on day 10, where the ferritin was 4969 g/l. He was discharged on day 12 with a creatinine of 371 µmol/L, and CRP 7mg/l and remained on tacrolimus. 48-year-old gentleman was admitted 11 days after having a DBD renal transplant for ESRF secondary to IgA nephropathy. The transplant itself was uneventful. His other past medical history comprised of transfusion dependent beta-thalassaemia intermedia (baseline ferritin was 2236 μg/L), and splenectomy. He was discharged on tacrolimus, mycophenolate mofetil and prednisolone. He was readmitted 6 days later with a 2-day history of dry cough, dyspnoea, and self-recorded pyrexia of 38°C. Examination revealed coarse crepitations predominantly on the right, saturations of 97% of room air, RR 18/min, BP 161/84 mmHg. Blood tests showed a ferritin 4054μg/l, CRP 84mg/l, and procalcitonin of 1.71mcg/L. CXR showed consolidation in the right mid and lower zones, and NPS confirmed SARS-CoV-2. Ceftriaxone was initiated. On day 2, his oxygen requirement increased with worsening bilateral mid zone air space shadowing. He was commenced on CPAP 5 days after admission and underwent endotracheal intubation on day 7. Given the clinical deterioration, and rising CRP (170 mg/l) he was commenced on anakinra 200mg intravenously once a day (Table 1) . Following initiation of anakinra, inotropes were weaned within 24 hours, and significant improvement in his blood parameters was noted (ferritin 2687 g/l, CRP 26 mg/l). His ICU admission was complicated by an Enterococcus faecium bacteraemia on day 9 of admission, for which he completed 7 days of teicoplanin. Anakinra was reduced and stopped after 21 days. Following a successful tracheostomy wean, he was discharged on day 45. A 68 year old woman with a background of non-Hodgkin's lymphoma (NHL) was re-admitted 2 weeks after being discharged with COVID-19. She has known follicular lymphoma stage 4A diagnosed in May 2018. She was treated with rituximab, last receiving a dose three months prior to her first admission. At the time of her first admission, she presented with a few weeks history of fever, myalgia and a sore throat. She had been given co-amoxiclav and azithromycin in the community, one week prior to admission. Her shortness of breath on exertion was deteriorating, and she was found to have saturations of 89%. NPS confirmed SARS-CoV-2, and her CXR was consistent with the diagnosis. She was managed on the ward with oxygen and intravenous antibiotics, and was discharged 3 weeks later, having had a CTPA confirming no pulmonary emboli, and a PET scan which showed no advancement of her NHL. She was readmitted 21 days later, with profound hypoxia, requiring intubation on arrival in hospital. A CTPA at the time showed extensive bilateral PEs with evidence of right heart strain. There were severe COVID related changes with widespread ground glass opacification throughout both lung fields. On admission, ferritin was 29784g/L, CRP 78 mg/l, and procalcitonin was 2.04 mcg/l. She was anaemic (Hb 100 g/l), but not cytopaenic, with platelets of 199 x10 9 /L, and a neurophilia of 15.9x10 9 /L. NPS and EDTA blood samples were positive for SARS-CoV-2. She was admitted to the ICU, initiated on intravenous tazocin and underwent thrombolysis for her PEs. The following day, ferritin rose to 40069 g/L, CRP was 109 mg/l, and procalcitonin increased to 9.85 mcg/l. Anakinra was initiated (Table 1) . She was initially started on 100mg four times a day, but due to pressures on the nursing staff this was changed to 200mg twice a day. Within 24 hours of intravenous anakinra, the ferritin improved to 20479 mcg/l (figure 1), and three days later continued to fall to 5118. A BioFire film was positive for Streptococcus pneumonia. Her ICU stay was complicated by worsening consolidation on her CXRs, necessitating a prolonged course of meropenem. She commenced ambisome on day 2 of admission, which was continued after a positive galactomannan test on her sputum and strongly positive βD Glucan (341.5 pg/ml), 2 weeks into her admission. It took 24 days from admission for the SARS-CoV-2 viraemia to disappear on both EDTA blood and NPS. She remains on ICU, and is currently weaning off the ventilator, with a tracheostomy-in-situ, and on minimal inotropic support. A 49-year-old lady presented with a 2-week history of non-productive cough and fever, with one week of diarrhoea. She has ESRF secondary to lupus nephritis, requiring haemodialysis. Her past medical history includes antiphospholipid syndrome, with thromboses; and ischaemic heart disease. Her medication included warfarin, and prednisolone. Initial blood tests showed an elevated CRP (339 mg/L), and ferritin (2890 µg/L), with bilateral patchy consolidation on CXR. She was admitted on 2 l/min oxygen via nasal cannula. Ceftriaxone and gentamicin were initiated, and SARS-CoV-2 was confirmed via NPS. On day 6, her oxygen requirements increased with worsening patchy consolidation bilaterally on CXR. She underwent endotracheal intubation on ICU, and her antibiotics were changed to temocillin, teicoplanin and gentamicin. On day 10, blood tests showed worsening thrombocytopenia and transaminitis with rising ferritin: Plt 91x10 9 /L, ferritin 7636 mcg/L, with a peak in her procalcitonin of 198mcg/L. An assumed diagnosis of HLH was made, and she commenced anakinra 200mg intravenously (Table 1) . She required increasing inotropic support and her thrombocytopaenia deteriorated with associated increasing ferritin over the following days. On day 17, blood tests revealed ferritin 30,086 mcg/L. A CT chest revealed small bilateral lower lobe pulmonary emboli, and extensive consolidation throughout both lungs. The clinical deterioration suggested worsening HLH, so anakinra was increased sequentially to 300mg twice a day, and antibiotics switched to meropenem and caspofungin. 2 days later, there was notable improvement in ferritin, CRP and the transaminases started to normalise. The patient remains intubated and ventilated, with reducing inotropic support. We present four cases of immunosuppressed patients, receiving beneficial effects from the use of intravenous anakinra to treat severe COVID-19 with hyperinflammation and concomitant bacterial infections. Careful consideration of the immunosuppressive treatment needs to factor in the ability to clear the virus without allowing for hyperinflammation. Anakinra has previously been used in the context of virally induced inflammatory conditions such as multicentric Castleman's disease; a reactive lymphoproliferative disorder typically described in HIV positive patients, with close association with HHV-8 (human herpes virus) (12). Cavalli et al (16) described the use of anakinra in patients with ARDS due to COVID-19, who also had hyperinflammation. They used intravenous anakinra at 5mg/kg twice a day (high dose group) for 21 days. A subgroup of patients received 100 mg subcutaneously twice a day (low dose group) for 7 days. Standard care included 400mg hydroxychlorquine, along with lopinavir and ritonavir. At 21 days, survival was 90% in the high-dose group and 56% in the standard treatment group (P= 0.009). Their lower threshold for diagnosis of hyperinflammation ((CRP >100 mg/L or ferritin 900 ng/ml), and differing standard practice, reflects a cohort of patients not necessarily classified as severe in the UK. A ferritin <500 ng/ml have a high negative predictive value for HLH (6), whereas >10000 mg/l is diagnostic of HLH in children (17) . The use of oral hydroxychloroquine may skew the mortality data, with a potential for increased cardiac complications (18) . An observational study on the use of hydroxychloroquine in COVID-19 did not report any difference in mortality (19) , and is not included in UK treatment algorithms. Furthermore, concomitant bacterial infections were excluded. Anakinra has received increasing use in the context of cytokine storm syndromes/HLH (4) . Although licensed subcutaneously, concerns over unreliable absorption in the critically ill patient, and the requirement of multiple injections, along with the support of its safety at higher doses in the context of sepsis, have all favoured intravenous administration. The support for our use of higher dose intravenous anakinra is further gained from the recent lack of benefit for the subcutaneous form in the context of COVID-19 (16) . The administration of anakinra intravenously leads to a maximum plasma concentration 24-29 times higher when compared to subcutaneous administration. It also has a shorter terminal half-life in the intravenous format as well (2.64 hrs compared to 5.24 hrs subcutaneously) (20, 21) , with the caveat that the subcutaneous half-life increases with greater adipose tissue. The intravenous form therefore enables a higher and faster maximal plasma concentration of anakinra; a trait that is desirable during cytokine storm syndromes. There is not sufficient evidence currently to suggest that the majority of patients with severe COVID-19 develop HLH, as the other diagnostic parameters not including ferritin (hypertriglyceridaemia, low fibrinogen, cytopaenias) do not correlate with severe disease (22) . None of our cases developed organomegaly, and only case 4 showed evidence of thromcoytopaenia, however the other blood count lineages did not fall. Therefore we believe we are treating hyperinflammation, and not HLH in our 4 cases. Timing of treatment with anakinra is one of the challenges in managing patients with COVID-19, and any clinical trial design. Whereas antiviral therapy is likely to be beneficial in the early phase of the disease, cytokine modulation and immunosuppressive therapy are most likely to have an impact at later stages (11) . A number of trials are attempting to answer this question. A recent large adaptiveplatform trial (Recovery trial) showed a significant mortality-benefit of low-dose dexamethasone, with the biggest risk-reduction in mortality observed in patients requiring invasive mechanical ventilation (23). This affirms the concept of the need for immune modulation in critically unwell patients requiring ventilatory and organ support. Further trials in the UK include REMAP-CAP (https://www.remapcap.org/); an adaptive-platform trial to assess the use of antibiotics, antivirals and immunomodulators in COVID-19. It offers the opportunity to explore targeted immune modulation therapy which will include interferon-beta-1a, IL-1 receptor antagonists (anakinra), tocilizumab and sarilumab (both anti-IL-6), all against placebo. COVACTA (https://clinicaltrials.gov/ct2/show/NCT04320615) randomized severe SARS-Cov-2 pneumonitis to tocilizumab (a monoclonal antibody targeting the IL6 receptor). CAN-COVID (https://clinicaltrials.gov/ct2/show/NCT04362813) randomises canikunimab (a monoclonal antibody https://mc.manuscriptcentral.com/rheumap which specifically targets the IL-1β cytokine ) to severe COVID-19, not requiring mechanical ventilation. The results of these trials will be extremely informative to direct treatment strategy for COVID -19 infections in the future. Whether single treatment, combination therapy, or early intervention are optimal remains to be elucidated. 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