O02 Persistent non-fulminant COVID-19 infection in a GPA patient on rituximab

Abstract Case report - Introduction Based on initial clinical data, it was suggested that patients with vasculitis who were immunosuppressed, would have a more severe COVID-19 infection. Here we present a case of a young 26-year old lady with granulomatosis with polyangiitis (GPA) on rituximab who developed COVID-19 infection while on active GPA treatment. Her COVID-19 infection confirmed on PCR serology, has been protracted but non-fulminant. She did not require mechanical respiratory support. At the same time her GPA remained active and worsened requiring further immunosuppression after she developed mild pulmonary haemorrhage. She is currently still receiving vasculitis treatment. Case report - Case description A 26-year-old lady with a background history of obstructive sleep apnoea and fibromyalgia was diagnosed with ENT-limited GPA in 2017. She was initially treated with azathioprine then methotrexate, and later switched to Rituximab in 2018 after she developed organ-threatening manifestations with bilateral hearing loss. She was stable on periodic infusions of rituximab at 6 to 9-monthly intervals and did not develop other organ-threatening features. She had been given one dose of rituximab for a flare of her GPA. In between rituximab doses, she was admitted with acute COVID-19 infection with related pneumonia and treated with antibiotics, fluids, and oxygen. Shortly after discharge, she was readmitted with worsening symptoms of non-resolving COVID-19 pneumonia which was evident on chest x-ray and levofloxacin treatment was initiated. Her condition improved and she was discharged. No mechanical respiratory support was required. She had her 2nd dose of rituximab after it had been delayed by about 2 weeks. She had been afebrile after the acute COVID-19 infection and her persistent positive results were explained as related viral shedding over a period of 8 weeks. One week later, she represented to hospital with fever, cough and shortness of breath, and her blood results showed a remarkable rise in inflammatory markers, including a CRP of 242. She was treated for non-resolving COVID-19 pneumonitis with worsening chest x-ray features. After hospital discharge, her GPA continued to flare with persistent epistaxis with nasal crusting. She also had worsening inflammatory arthritis with purpuric rash on her legs. An ENT review confirmed nasal septum perforation, but no renal involvement was found. Additional cyclophosphamide was commenced via the day-case unit. Her SARS-CoV-2 serology was negative prior to commencing cyclophosphamide. She is now SARS-CoV-2 positive after two doses of cyclophosphamide, but she is afebrile and stable. Case report – Discussion COVID-19 infection carries a high mortality rate in patients with multiple co-morbidities, but recent literature suggests that patients on immunosuppressants may not actually have fulminant COVID-19 disease. This case illustrates the challenges of treating active vasculitis in the context of ongoing COVID-19 infection. Her vasculitis remained active requiring escalation of immunosuppression with caution, while she was concomitantly fighting SARS-CoV-2 and superadded bacterial infection. A similar case has been published by Guilpain et al of a 52-year-old woman with PR3-ANCA vasculitis on maintenance therapy with rituximab and low-dose prednisone who developed COVID-19 infection. They reported milder evolution of COVID-19 infection in comparison with previous reports. It is now well known that some disease-modifying anti-rheumatic drugs (DMARDs) such as tocilizumab, hydroxychloroquine and tofacitinib could suppress the cytokine profile seen in severe COVID-19 infection. In addition, several case reports have even reported possible protective effect of immunosuppressants against severe complications of COVID-19 in patients with rheumatological and non-rheumatological conditions. Another complexity in this case was monitoring the disease progression, since both COVID-19 and GPA can have similar findings on chest CT scan of ground glass opacity. In order to better understand the role of immunosuppressants in rheumatological patients with COVID-19 infection, more data is required, currently European League Against Rheumatism (EULAR) is collecting data to monitor and report outcomes of COVID-19 in adult and paediatric population, this will provide invaluable insight for Rheumatologists. Case report - Key learning points 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.

more difficult bone mars of diagnostic . Persistent inallreleanakinra, her well above the the pandemic. She subsequently had a negative bone marrow biopsy in line with >50% of critical care patients with sHLH; a demonstration that biopsy proven haemophagocytosis is not necessary for a clinical diagnosis of sHLH. No other sHLH trigger was found. Early recognition and intensive treatment may have contributed to the positive outcome; sHLH mortality in ICU patients can reach nearly 70%. These decisions were facilitated by early discussion with MDT members of HASC. The initial dose of 70mg IV BD and speed of wean after an effective dose was achieved were insufficient. A longer period on 400mg anakinra daily, a slower wean, plus addition of methylprednisolone, IVIG and cyclosporin appeared to aidthe resolution of her relapse. Case report -Key learningpoints COVID-19 infection is complicated by hyperinflammatory syndromes (cytokine storm, PIMS-TS, sHLH) in a significant minority of patients.
In the absence of a treatment for COVID-19, early recognition of treatable complications should be a clinical priority. Adult clinicians should be aware of PIMS-TS which may rarely occur in young adults, especially those of African descent. The CDC definition extends to those aged up to 21. Cardiac aneurysms should be actively excluded in this group. The challenges associated with sHLH diagnosis became more apparent during the peak of the COVID-19 pandemic where key tests were difficult to obtain. Current scoring systems are insensitive for evolving sHLH. A high index of clinical suspicion and a multidisciplinary team approach, in which rheumatologists are key, is important for early recognition and treatment. Although no other sHLH trigger was found in this case, we have seen COV-HLH patients with underlying connective tissue disorder, haematological malignancy or a primary genetic defect, which should be considered if COV-HLH patients do not respond to treatment. Optimal treatment for sHLH and the hyperinflammatory syndromes associated with COVID-19 is not supported by randomised controlled trials but there is accumulating evidence for anakinra. Whilst its use in sHLH remains off-license, UK guidelines have been developed, with an emphasis on early and high dose treatment. Careful anakinra weaning regimens should be considered and patient progress regularly reviewed to avoid relapse of sHLH and subsequent readmission. Our patient also appeared to have a favourable response to corticosteroid and other combined immunosuppressive treatments including IVIG and cyclosporine. It remains to be seen if the incidence of adult-onset PIMS-TS and COV-HLH will reduce now that Dexamethasone is standard of care in adult patients with COVID-19.

Gurpreet Kaur, Alaeldin Nour and Kehinde Sunmboye
Rheumatology: University Hospitals of Leicester, Leicester, United Kingdom Case report -Introduction: Based on initial clinical data, it was suggested that patients with vasculitis who were immunosuppressed, would have a more severe COVID-19 infection. Here we present a case of a young 26-year old lady with granulomatosis with polyangiitis (GPA) on rituximab who developed COVID-19 infection while on active GPA treatment. Her COVID-19 infection confirmed on PCR serology, has been protracted but non-fulminant. She did not require mechanical respiratory support. At the same time her GPA remained active and worsened requiring further immunosuppression after she developed mild pulmonary haemorrhage. She is currently still receiving vasculitis treatment.
Case report -Case description: A 26-year-old lady with a background history of obstructive sleep apnoea and fibromyalgia was diagnosed with ENT-limited GPA in 2017. She was initially treated with azathioprine then methotrexate, and later switched to Rituximab in 2018 after she developed organ-threatening manifestations with bilateral hearing loss. She was stable on periodic infusions of rituximab at 6 to 9-monthly intervals and did not develop other organ-threatening features. She had been given one dose of rituximab for a flare of her GPA. In between rituximab doses, she was admitted with acute COVID-19 infection with related pneumonia and treated with antibiotics, fluids, and oxygen. Shortly after discharge, she was readmitted with worsening symptoms of non-resolving COVID-19 pneumonia which was evident on chest x-ray and levofloxacin treatment was initiated. Her condition improved and she was discharged. No mechanical respiratory support was required. She had her 2 nd dose of rituximab after it had been delayed by about 2 weeks. She had been afebrile after the acute COVID-19 infection and her persistent positive results were explained as related viral shedding over aperiod of 8weeks. One week later, she represented to hospital with fever, cough and shortness of breath, and her blood results showed a remarkable rise in inflammatory markers, including a CRP of 242. She was treated for nonresolving COVID-19 pneumonitis with worsening chest x-ray features. After hospital discharge, her GPA continued to flare with persistent epistaxis with nasal crusting. She also had worsening inflammatory arthritis with purpuric rash on her legs. An ENT review confirmed nasal septum perforation, but no renal involvement was found. Additional cyclophosphamide was commenced via the day-case unit. Her SARS-CoV-2 serology was negative prior to commencing cyclophosphamide. She is now SARS-CoV-2 positive after two doses of cyclophosphamide, but she is afebrile and stable. It is now well known that some disease-modifying anti-rheumatic drugs (DMARDs) such as tocilizumab, hydroxychloroquine and tofacitinib could suppress the cytokine profile seen in severe COVID-19 infection. In addition, several case reports have even reported possible protective effect of immunosuppressants against severe complications of COVID-19 in patients with rheumatological and non-rheumatological conditions. Another complexity in this case was monitoring the disease progression, since both COVID-19 and GPA can have similar findings on chest CT scan of ground glass opacity. In order to better understand the role of immunosuppressants in rheumatological patients with COVID-19 infection, more data is required, currently European League Against Rheumatism (EULAR) is collecting data to monitor and report outcomes of COVID-19 in adult and paediatric population, this will provide invaluable insight for Rheumatologists.

Case report -Key learningpoints
. 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.

St George's University Hospitals NHS Foundation Trust, London, United Kingdom
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 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