key: cord-0757633-8jrqokld authors: Stephen, Shiny; Park, Yeung‐Ae; Chrysostomou, Anastasia title: Clinical benefits of Tocilizumab in COVID‐19‐related cytokine release syndrome in a patient with end‐stage kidney disease on haemodialysis in Australia date: 2020-08-10 journal: Nephrology (Carlton) DOI: 10.1111/nep.13767 sha: d7e643657358e24b4e245d13023cbee4ef4853e7 doc_id: 757633 cord_uid: 8jrqokld COVID‐19 remains a global pandemic with more than ten million cases and half a million deaths worldwide. The disease manifestations in patients with chronic kidney disease and especially those on haemodialysis are still being understood, with only a few overseas case series, and small observational trials thus far. It appears the disease is more severe in this patient cohort. (1) (1) (1 1) Part of the pathophysiology of severe COVID‐19 is related to accompanying cytokine release syndrome. Tocilizumab, an interleukin‐6 inhibitor, has been trialled for treatment of cytokine release syndrome in COVID‐19, but not yet approved. We present a case of an Australian patient on long‐term haemodialysis with severe COVID‐19 who was successfully treated with Tocilizumab. The peak of her illness was on day 7, with a C‐reactive protein of 624 mg/L (reference <5 mg/L), ferritin of 5293 ng/mL (reference 30‐500 ng/mL), and interleukin‐6 level 1959.7 pg/mL, consistent with cytokine release syndrome. She was severely hypoxic on a ventilator, with rising inotropic requirements. With the use of Tocilizumab there was a significant and immediate response in her inflammatory markers, and she made a steady recovery. The patient was discharged home six weeks after presentation. atrial fibrillation on amiodarone, hypertension, dyslipidaemia and an inguinal hernia repair two weeks prior. At the time of presentation (Day 0), she was found to have thrombosis of her arteriovenous fistula (AVF) and was unable to undergo dialysis. She was admitted to hospital and underwent a surgical revision of the fistula that evening. Despite her upper respiratory tract symptoms, the patient appeared well, was afebrile, and all her vital signs were within normal limits. She reported no epidemiological criteria for COVID-19, including no close contact with a confirmed case or recent travel, but received a nasopharyngeal swab for COVID-19 as part of theatre protocol. The next evening, she spiked a fever of 39.4 degrees Celsius and was commenced on intravenous Ceftriaxone and Azithromycin for a community-acquired pneumonia. On day 2, whilst undergoing dialysis through her revised fistula, she had more fevers associated with rigors and complained of severe "bone pain". Her antibiotics were changed to intravenous Piperacillin-Tazobactam, Azithromycin and Vancomycin to cover for possible bacteraemia post-AVF revision. She was lymphopaenic at 0.4x10 9 /L (reference 1.0-3.5x10 9 /L), and C-reactive protein (CRP) was 80mg/L (reference <5mg/L). Influenza A/B, respiratory syncytial virus and rhinovirus PCR, urine atypical pneumonia screen, serial blood cultures and urine were unremarkable. Chest radiograph revealed mild left perihilar interstitial type opacity as well as left upper lobe opacity consistent with developing consolidation ( Figure 1A ). That evening, the patient became hypoxic, with oxygen saturations dropping to 89% on room air, febrile at 40.3 degrees Celsius, and hypotensive with a blood pressure (BP) of 87/50 mmHg (baseline systolic BP around 110mmHg). She was transferred to the Intensive Care Unit (ICU) for inotropic support. Two SARS-COV2 PCR swabs returned positive and the patient clinically deteriorated rapidly requiring intubation on day 6 of admission, at which time nasogastric feeds were also commenced. Chest radiographs demonstrated rapid daily progression and increased volume of bilateral extensive consolidation with subpleural sparing, suggestive of acute respiratory distress syndrome (ARDS) ( Figure 1B ). Around day 7 of admission, her CRP rose to 624mg/L (reference <5mg/L), erythrocyte sedimentation rate (ESR) was >100mm/hr (reference 5-20mm/hr), interleukin-6 (IL-6) level was significantly elevated at 1959.7pg/mL (reference 0.0-149.0pg/mL), ferritin was 5293ng/ml (reference 30-500ng/ml), fibrinogen 7.8g/L (reference 2.0 -4.5 g/L) (Figure 2, Figure 3 ) and she desaturated to 73% on 100% supplemental oxygen at 40L/min with positive end-expiratory pressure (PEEP) of 15cmH2O. The clinical picture and investigation results were consistent with cytokine release syndrome (CRS) and the patient was critically ill. After a multi-disciplinary discussion involving the Renal, Haematology, Infectious Diseases and ICU teams, she was administered two doses of Tocilizumab 8mg/kg (450mg) intravenously 12 hours apart as well as Hydroxychloroquine 400mg BD. The latter was ceased 3 days later due to QTc prolongation (490ms). She was also commenced on Nitric Oxide up to 40ppm and prone positioning was used for 12-16 hours from day 8. At the peak of her inotropic supports, the patient required 30 microg/hr of Noradrenaline with 2.4units/hr of Vasopressin to aim for a mean arterial pressure of 65mmHg. While the initial target for fluid balance was negative 3L, this could not be achieved without further incrementing the inotropic requirement. Thus, the aim was changed to an even balance, but even this was proving challenging despite continuous veno-venous haemodiafiltration. At 9 hours post the first Tocilizumab dose, the CRP had already fallen from 624mg/L to 576mg/L. Within 72 hours (day 11), the CRP fell to 72mg/L (Figure 3) , oxygenation improved to 96% with FiO2 30% and oxygen flow of 50L/min, and sedation was able to be weaned off. Inotropic supports were weaned off on day 18, and the patient was extubated. She was discharged from ICU to the ward on day 21, saturating at 99% on 2L of oxygen by nasal prongs. Other minor issues during the ICU admission included anaemia requiring intermittent blood transfusion in the setting of withheld erythropoietin stimulating agent, and the development of a Stage 1 heel pressure ulcer. On discharge to the ward, she required physiotherapy and alternate-daily haemodialysis with BP support using pre-dialysis Midodrine at 5mg and 20% concentrated albumin for fluid overload. The patient walked out of hospital 6 weeks post admission, and has had two negative COVID-19 PCR tests 8 weeks from her initial positive result. COVID-19 caused by SARS-COV2 has affected more than ten million cases with 500,000 deaths worldwide as of 4 July 2020 1 . While most patients experience mild respiratory illness, 15% present with moderate to severe pneumonia and 5% require intensive supports for critical illness 2 . A recent meta-analysis demonstrated chronic kidney disease to be associated with greater risk of severe COVID-19 infection 3 . While management is largely supportive, many disease-modifying treatments such as anti-virals and immunosuppressants are in investigation, but not yet adopted into formal guidelines for treatment in Australia as per the National COVID-19 Clinical Evidence Taskforce. Tocilizumab, a humanised anti-IL-6 antibody, has been used safely and effectively in the treatment of rheumatological conditions, as well as to deter CRS caused by CAR-T cell antibody-based immunotherapy 4, 5 . The rationale for use in severe COVID-19 comes from autopsy assessments of ARDS-related lung damage in COVID-19 as well as blood samples of critically ill COVID-19 patients indicating CRS to be a major culprit 6, 7 . CRS is an excessive, unregulated inflammatory response, with increased production of cytokines such as IL-6. Pathogenic Th1 cells and inflammatory monocytes (with high expression of IL-6) have been isolated from the peripheral blood of COVID-19 patients, and in larger numbers in critically ill patients 8 . The most dramatic period of clinical deterioration in our patient coincided with the highest CRP, ferritin, and IL-6 levels, strongly indicating the role of CRS in her illness trajectory. Her mortality at this point would have been high, based on the findings of a retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China. They showed that higher levels of ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p<0·001) and IL-6 (p<0·0001) were associated with higher mortality 9 . A prospective trial in Italy with 100 patients with COVID-19 needing ventilatory support who received Tocilizumab either in ICU or on the ward (when ICU beds were to capacity), found an improvement or stabilisation in respiratory condition in 77% of patients, and worsening in 23% patients, of whom 20% died 10 . COVID-19 in dialysis patients is not as well described or understood. A case series in Italy recorded a very high mortality of 41% in a haemodialysis population, compared with a mortality of 10% in nonchronic kidney disease (CKD) patients 11 . Postulated reasons for increased risk of severe COVID-19 infections in CKD patients include cardiac and other comorbidities, as well as a relative immunocompromised state 12, 13 . Perhaps CKD patients are also prone to CRS due to their chronic inflammatory state, making them more susceptible to severe disease. Severe cases in the Italian case series were treated with Hydroxychloroquine and/or antiretroviral therapies based on the discretion of an infectious diseases specialist, but none of the patients received Tocilizumab. A haemodialysis case in the United States managed with Tocilizumab had a successful outcome, but its use coincided with the introduction of broad-spectrum antibiotics, which may have been a confounder 14 . In the case of our patient, the only significant therapeutic change in the 9 hours between the peak of her CRP and the first detected fall in CRP, apart from use of nitric oxide, was the introduction of Tocilizumab. There are case reports 15, 16 emerging of the use of continuous renal replacement therapy with extracorporeal blood purification technology to remove inflammatory cytokines such as CRP, IL-1 and IL-6, instead of the use of Tocilizumab, which is IL-6 specific. These strategies have had some reported success. Our case did not use this technique. A retrospective observational study has just completed in China, and results are awaited 17 . In conclusion, we describe a case of successful recovery from CRS secondary to COVID-19 with Tocilizumab in a critically ill elderly patient on longterm haemodialysis. Tocilizumab, an IL-6 inhibitor, may be useful as a rescue therapy for CRS secondary to severe COVID-19 even in haemodialysis patients, who have severely elevated inflammatory markers including CRP and ferritin, and increasing ventilation requirements such as our case. We await current and future randomised controlled trials to shed further light on this. 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Authors declare no competing interests.We would like to thank the staff working in the Dialysis Unit at Epworth Richmond for their dedicated care of this patient as well as coping with the challenges of rigorous COVID-19 precautions. A special word of thanks to the nurse unit manager Ms. Emma Taylor, for her tireless work in this.We also thank the other Epworth Hospital staff, including the ICU, Infectious Diseases and Haematology teams who helped to provide exceptional care for this seriously ill patient.