O03 A case of hyperinflammatory COVID-19 that responded to tocilizumab therapy

Abstract Case report - Introduction Coronavirus disease 19 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), has reached pandemic level and led to over 46,000 deaths in the UK. COVID-19 is primarily a respiratory illness and 10-20% of infected individuals develop severe disease with interstitial pneumonia or acute respiratory distress syndrome (ARDS). In this subgroup of patients, severe clinical manifestations are postulated to result from a hyperactive immune response. This has led to the proposal that immunomodulatory medications could be used for the treatment of COVID-19. Here, we report a case of COVID-19 that was treated with the IL-6 inhibitor, tocilizumab. Case report - Case description A 54-year-old Middle Eastern woman presented to A&E with a one-week history of fever, cough, headache and ageusia. Her past medical history was significant for asthma, chronic headaches, gastro-oesophageal reflux syndrome and subarachnoid haemorrhage. On presentation, she had a low-grade temperature (37.8 °C) but her observations were otherwise normal, and her oxygen saturations were 99% on room air. Examination revealed right basal chest crackles. Bloods showed a mild lymphopenia (0.9x109/l) and a raised CRP (82mg/l) and a chest radiograph demonstrated bibasal shadowing. The patient was diagnosed with probable COVID-19 and discharged with a course of oral doxycycline and a plan for review in the ambulatory unit the following day. When reviewed the next day, her oxygen saturations had fallen to 90% on room air. At this point, her SARS-CoV-2 assay had been resulted as positive and a decision was made to admit her for oxygen therapy. The patient continued to deteriorate despite optimal supportive therapy and the addition of intravenous benzylpenicillin for possible superadded bacterial infection. On day 7 of admission, her respiratory rate was 32-38 breaths per minute, and she required 13l/min of oxygen. Her bloods revealed CRP 474mg/L, D dimer >6000 ng/ml, ferritin 224 μg/L, neutrophils 9.5x109/l and lymphocytes 0.6 x109/l. There were no signs of superadded bacterial infection despite a thorough infection screen. Given her clinical deterioration, she was reviewed by the critical care team for consideration of transfer to higher-level care. The ward team decided to administer a single dose of the anti-IL-6 agent tocilizumab for the treatment of a cytokine storm secondary to COVID-19 infection. Within 24 hours of tocilizumab treatment, her oxygen requirements fell to 5l/min and her work of breathing significantly improved. On day 15 of admission, she was discharged with saturations of 92% on room air. Case report - Discussion The patient described in this case showed significant clinical deterioration with features suggestive of cytokine storm secondary to COVID-19. IL-6 is thought to be a key cytokine responsible for initiating the acute phase response and we postulate that IL-6 levels were raised in this patient. Unfortunately, we did not have the assay available to measure this. The treating clinical team decided to prescribe a single dose of tocilizumab on a compassionate use basis. This resulted in a rapid clinical improvement and the patient was subsequently discharged without the need for intensive care. In this case, we propose that tocilizumab inhibited further cytokine activation and prevented the positive feedback loop of inflammation that can otherwise result in rapid clinical deterioration. There are several interesting points to be noted from this case. In this patient, tocilizumab resulted in a rapid reduction in CRP levels. This is thought to correspond to the inhibition of IL-6 mediated release of acute phase proteins by the liver. Therefore, it should be noted that post-tocilizumab treatment, patients should be closely monitored for superadded bacterial infection as they may not mount a full immune response. Larger trials of tocilizumab for the treatment of COVID-19 are currently underway and are required to confirm the efficacy of IL-6 inhibition for COVID-19. The phase III COVACTA trial of tocilizumab in COVID-19 patients did not meet its primary endpoint of improved clinical status however a trend towards shorter hospital admissions was seen. Further studies are ongoing to investigate the role of tocilizumab in other treatment settings, including in combination with an antiviral medication. Further information is required to determine which patients should receive immunomodulatory medications and at which point in their illness. Data is also needed to understand the most efficacious dosing regimen for tocilizumab and its side-effect profile in COVID-19 patients. Case report - Key learning points The COVID-19 pandemic has affected millions of people worldwide and has led to an unprecedented effort from the scientific community to understand the pathophysiology of the disease and to find effective treatments. Emerging evidence suggests that SARS-CoV-2 can induce a hyperactive immune response in a subgroup of patients who develop highly elevated levels of acute phase proteins. It has been proposed that the overactive immune response is responsible for some of the severe clinical manifestations seen and this has led to the suggestion that immunomodulatory medications could be used for the treatment of COVID-19. Indeed, dexamethasone has been shown to be an effective treatment and other immunomodulatory medications including hydroxychloroquine, the IL-1 inhibitor anakinra and JAK-kinase inhibitors are currently being trialled for the treatment of COVID-19. This case highlights the clinical and biochemical features of a patient who developed features suggestive of a cytokine storm secondary to COVID-19 and who responded to treatment with the IL-6 inhibitor tocilizumab. Further work is required to understand the role of immunomodulatory medications for the management of COVID-19 infection.

. This case poses a challenge for Rheumatologists in managing a patient with active vasculitis and concomitant COVID-19 infection due to limited data available literature. . It has also stressed the importance of working in a multidisciplinary team when managing such complex patients. . Importance of continuous surveillance of patients receiving immunosuppressive therapy is advised due to possible increased risk to SARS-CoV-2.

Kathryn Biddle, Daniel Burrage and Nidhi Sofat
St George's University Hospitals NHS Foundation Trust, London, United Kingdom Case report -Introduction: Coronavirus disease 19 , caused by Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), has reached pandemic level and led to over 46,000 deaths in the UK. COVID-19 is primarily a respiratory illness and 10-20% of infected individuals develop severe disease with interstitial pneumonia or acute respiratory distress syndrome (ARDS). In this subgroup of patients, severe clinical manifestations are postulated to result from a hyperactive immune response. This has led to the proposal that immunomodulatory medications could be used for the treatment of COVID-19. Here, we report a case of COVID-19 that was treated with the IL-6 inhibitor, tocilizumab.
Case report -Case description: A 54-year-old Middle Eastern woman presented to A&E with a one-week history of fever, cough, headache and ageusia. Her past medical history was significant for asthma, chronic headaches, gastro-oesophageal reflux syndrome and subarachnoid haemorrhage. On presentation, she had a low-grade temperature (37.8 C) but her observations were otherwise normal, and her oxygen saturationswere99%onroomair.Examinationrevealed right basal chest crackles. Bloods showed a mild lymphopenia (0.9x10 9 /l) and a raised CRP (82mg/l) and a chest radiograph demonstrated bibasal shadowing. The patient was diagnosed with probable COVID-19 and discharged with a course of oral doxycycline and a plan for review in the ambulatory unit the following day. When reviewed the next day, her oxygen saturations had fallen to 90% on room air. At this point, her SARS-CoV-2 assay had beenresultedas positive andadecision wasmade toadmitherforoxygen therapy.
The patient continued to deteriorate despite optimal supportive therapy and the addition of intravenous benzylpenicillin for possible superadded bacterial infection. On day 7 of admission, her respiratory rate was 32-38 breaths per minute, and she required 13l/min of oxygen. Her bloods revealed CRP 474mg/L, D dimer >6000 ng/ml, ferritin 224 lg/L, neutrophils 9.5x10 9 /l and lymphocytes 0.6 x10 9 /l. There were no signs of superadded bacterial infection despite a thorough infection screen. Given her clinical deterioration, she was reviewed by the critical care team for consideration of transfer to higher-level care. The ward team decided to administer a single dose of the anti-IL-6 agent tocilizumab for the treatment of a cytokine storm secondary to COVID-19 infection.
Within 24 hours of tocilizumab treatment, her oxygen requirements fell to 5l/min and her work of breathing significantly improved. On day 15 of admission,she was dischargedwith saturationsof 92% onroom air.
Case report -Discussion: The patient described in this case showed significant clinical deterioration with features suggestive of cytokine storm secondary to COVID-19. IL-6 is thought to be a key cytokine responsible for initiating the acute phase response and we postulate that IL-6 levels were raised in this patient. Unfortunately, we did not have the assay available to measure this. The treating clinical team decided to prescribe a single dose of tocilizumab on a compassionate use basis. This resulted in a rapid clinical improvement and the patient was subsequently discharged without the need for intensive care. In this case, we propose that tocilizumab inhibited further cytokine activation and prevented the positive feedback loop of inflammation that can otherwise result in rapid clinical deterioration. There are several interesting points to be noted from this case. In this patient, tocilizumab resulted in a rapid reduction in CRP levels. This is thought to correspond to the inhibition of IL-6 mediated release of acute phase proteins by the liver. Therefore, it should be noted that post-tocilizumab treatment, patients should be closely monitored for superadded bacterial infection as they may not mount afull immune response. Larger trials of tocilizumab for the treatment of COVID-19 are currently underway and are required to confirm the efficacy of IL-6 inhibition for COVID-19. The phase III COVACTA trial of tocilizumab in COVID-19 patientsdidnotmeetitsprimaryendpoint ofimprovedclinicalstatus however a trend towards shorter hospital admissions was seen. Further studies are ongoing to investigate the role of tocilizumab in other treatment settings, including in combination with an antiviral medication. Further information is required to determine which patients should receive immunomodulatory medications and at which point in their illness. Data is also needed to understand the most efficacious dosing regimen for tocilizumab and itsside-effect profile inCOVID-19 patients.
Case report -Key learning points: The COVID-19 pandemic has affected millions of people worldwide and has led to an unprecedented effort from the scientific community to understand the pathophysiology of the disease and to find effective treatments. Emerging evidence suggests that SARS-CoV-2 can induce a hyperactive immune response in a subgroup of patients who develop highly elevated levels of acute phase proteins. It has been proposed that the overactive immune response is responsible for some of the severe clinical manifestations seen and this has led to the suggestion that immunomodulatory medications could be used forthe treatment of COVID-19. Indeed, dexamethasone has been shown to be an effective treatment and other immunomodulatory medications including hydroxychloroquine, the IL-1 inhibitor anakinra and JAK-kinase inhibitors are currently being trialled for the treatment of COVID-19. This case highlights the clinical and biochemical features of a patient who developed features suggestive of a cytokine storm secondary to COVID-19 and who responded to treatment with the IL-6 inhibitor tocilizumab. Further work is required to understand the role of immunomodulatory medications for the management of COVID-19 infection.

Zoe Rutter-Locher, Bhashkar Mukherjee, Thomas Mason and Begona Lopez
Guy's and St Thomas' NHS Trust, London, United Kingdom Case report -Introduction: By June 2020, 175,000 cases of COVID-19 had been identified in London alone. The most common symptoms include fever, headache, loss of smell, cough, myalgia, and sore throat. The major complication is acute respiratory distress syndrome (ARDS) but systemic complications such as cardiomyopathy, acute kidney injury, encephalopathy and coagulopathy are being identified. A delayed multi-system inflammatory syndrome in children has also been recognised and further complications are likely to be identified as our experience increases. Here, we report the case of a patient with large vessel vasculitis who initially presented with symptoms highly likely to be due to COVID-19infection.
Case report -Case description: A 36-year-old black African nurse presented in May 2020, with acute onset 7 days prior of high-grade fevers, rigors, nights sweats, generalised myalgia, sore throat, headache with photophobia, anosmia, dysgeusia and a widespread rash. She was a smoker with no other relevant medical, travel nor sexual history, and no drug use. A COVID-19 swab on day 2 had been negative and she had taken acourse of Doxycycline. Examination revealed firm palpable subcutaneous nodules on lower limbs, upper back and forehead and cervical lymphadenopathy. She was photophobic with no meningism. The rest of her physical examination was normal. BP was 116/97 mmHg, heart rate 109 bpm and satO2 100%. Investigations demonstrated C-reactive protein 330mg/L, erythrocyte sedimentation rate 140, Ferritin 479, lymphopaenia 0.7x10 9 , eGFR 54 with no haematoproteinuria, D-dimer 3.05 mg/L with INR 1.1, aPTT 1.3, fibrinogen 8.8 g/L. Hb, WCC, liver function, CK, serum ACE and triglycerides were normal. Infectious screen revealed negative blood cultures, HIV, Hepatitis B and C, EBV, CMV and Treponema pallidum serology. CT brain and CSF analysis were normal including bacterial culture and viral PCR. ANA, ENA, dsDNA, ANCA and aPL antibodies were negative with normal complement levels. Throat swab grew group A streptococcus and she was treated with broad spectrum antibiotics for 7 days maintaining fevers up to 39 o C. Skin biopsy was non-specific with negative direct immunofluorescence but showed microvascular thrombi in the papillary dermis. COVID-19 PCR tests (three naso-pharyngeal swabs and one stool PCR) and IgG test (day 38) were negative. CT showed no pneumonitis but non-specific retroperitoneal stranding with medium/large vessel vasculitis involving both proximal renal arteries and a 6 cm segment of mid abdominal aorta on PET-CT. We started oral prednisolone 40mg with immediate resolution of her fevers, myalgia, and inflammatory markers, remaining well a month later. Case report -Discussion: Takayasu's arteritis is the most common autoimmune large vessel vasculitis (LVV) affecting young females and involves inflammation of the arterial wall ultimately resulting in stenosis and obstruction of the vessel. However, it is rare in patients with African heritage and usually presents with a prolonged prodromal phase. Given the atypical presentationand symptoms consistent with COVID-19infection we feel that this patients' LVV may have been a complication of COVID-19 infection. The relationship between infections and vasculitis is complex. TB and syphilis cause aortitis and a relationship between infection and vasculitis has been proven in HBV associated PAN and HCV associated cryoglobulinemia. Experimental data supports a possible association between CMV and herpes virus and Takayasu arteritis. It could, therefore, be hypothesised that COVID-19 infection can trigger LVV. Our patient had a throat swab positive for Streptococcus pyogenes which is an uncommon cause of infective endocarditis and mycotic aneurism, but this patient had no evidence of either endocarditis or aneurism formation and so it was felt the throat swab finding was incidental. Our patient had repeated negative COVID-19nasopharyngeal swabs and a negative antibody test at day 38. Although this argues against a diagnosis of COVID-19 related illness, the relative lack of information we currently have regarding sensitivities of the tests, at what point COVID-19 PCR becomes negative in the illness and when/if patients develop antibodies, means these negative tests in the presence of typical symptoms cannot exclude the diagnosis. We believe thiscase isextremely important tohighlight apossiblenovelinflammatory complication of COVID-19 infection. We decided to treat this patient in line with guidance for the management of LVV, including the introduction of methotrexate, but it will be interesting to observe her long-term outcome.
Case report -Key learningpoints . Increasing numbers of COVID-19 related systemic inflammatory conditions are likely to be recognised over the coming months. We present the case of patient with large vessel vasculitis who initially presented atypically with symptoms consistent with COVID-19 infection . To identify these complications, COVID-19 symptoms questioning should be part of any routine medical history . More information is required regarding the sensitivity of COVID-19 PCR and antibody tests to aid the diagnosis of these conditions . The long-term management of inflammatory conditions associated with COVID-19 infection is not clear and a discussion is warranted as to whether DMARDs should be initiated Case report -Introduction: Behcet's disease is a rare chronic multiorgan inflammatory disorder characterized by oral aphthous and genital ulceration, often associated with several systemic manifestations. These include skin lesions, arthritis, ocular disease, CNS, GI, and vascular involvement. Arterial disease can affect medium and large sized arteries, leading to aneurysm development with the potential to rupture. We report a case of Behcet's disease presenting in such a manner, with multiple aneurysms at imminent risk of arterial rupture. The presentation occurred at the peak of the COVID-19 pandemic, in April 2020 with the patient contracting the virus complicating cyclophosphamide immunosuppression therapypost operatively.
Case report -Case description: A 54-year-old man had been under rheumatology follow up for numerous years. He reported recurrent oral ulcers, and episodic fevers. He previously had confirmed cerebral sinus thrombosis, aseptic endocarditis, multiple pulmonary emboli and was investigated for inflammatory boweldisease. HepresentedacutelytoAE withapainful,tenderleftcalf andalargepulsatile mass in the calf. He reported paraesthesia in his left leg/foot suggestive of nerve compression. CT angiogram performed, revealed a large 6.5cm x 4cm left tibioperoneal trunk (TPT) pseudoaneurysm (Fig.1), and 1.2cm right anterior tibial (ATA) pseudoaneurysm (Fig 2). There was also a 3.8cm infrarenal inflammatory abdominal aortic pseudoaneurysm (Fig 3), and finally a 2.3cm right lower lobe pulmonary artery aneurysm. Laboratory investigations revealed raised inflammatory markers, with ESR of 120 and CRP 73. A diagnosis of vascular Behcet's was suspected. Urgent surgical intervention was deemed necessary to prevent limb and life-threatening complicationsof arterial rupture. He underwent opensurgical decompression and graft repair of the left TPT aneurysm. Endovascular stenting of infrarenal AAA was performed and the right ATA aneurysm was ligated and excised. The pulmonary artery aneurysm was managed conservatively, but interval CT Imaging post immunosuppression treatment showed complete resolution. This undoubtedly was due to immunosuppression therapy. The first cyclophosphamide and methylprednisolone infusion were given day 1 post-op. The following day he developed a fever and a dry cough. He subsequently tested positive for SARS-COV-2. This was at the height of the COVID-19 pandemic. He required supplementary oxygen, but his condition did not deteriorate further, and he made a complete recovery. A difficult dilemma was posed between immunosuppression and the risk of infection having been diagnosed with COVID-19. An MDT approach was adopted, and input was sought from the Birmingham Bechet's centre of excellence. He continued immunosuppressive treatment once recovered from the virus. Case report -Discussion: Bechet's disease is considered a form of systemic vasculitis and is unique in its ability to involve blood vessels of all sizes from the arterial and venous systems. Vascular manifestations in Bechet's disease are associated with increased mortality and morbidity with manifestations more common in men. Arterial rupture is the leading cause of sudden death in patients with Bechet's disease. Endovascular and perivascular inflammation of large vessels can lead to haemorrhage, aneurysm formation with risk of rupture, stenosis, and thrombus development.
To prevent potential life-threatening complications of vascular Bechet's, a combination of surgical/radiological and medical management is often required. High dose corticosteroids and cyclophosphamide infusions are typically used, with aim to achieve disease remission. It is recommended that if surgical/radiological interventions are indicated, it should ideally be performed when the disease is quiescent. However, urgent