key: cord-0931299-e84q0xex authors: García-Hernández, R.; Espigares-López, M. I.; Miralles-Aguiar, F.; Gámiz-Sánchez, R.; Arroyo Fernández, F. J.; Pernia Romero, A.; Torres, L. M.; Calderón Seoane, E. title: Immunomodulation using CONVEHY® for COVID-19: from the storm to the cytokine anticyclone date: 2021-02-15 journal: nan DOI: 10.1016/j.redare.2020.08.007 sha: ed1e582db65c22a35357cacb54258fa1569ac9d1 doc_id: 931299 cord_uid: e84q0xex nan análisis e interpretación de los datos, proyecto de artículo o revisión crítica del contenido Intelectualmente, la aprobación final de la versión presentada. Los autores aprecian el trabajo de todos los trabajadores de la salud en la Unidad de Cuidados Críticos Quirúrgicos. Hospital Universitario Puerta del Mar. Cádiz. España. The cause of the COVID-19 pandemic is severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection. Severe forms of the disease occur predominantly in older adults or in individuals with underlying medical comorbidities, such as cardiovascular disease, hypertension, diabetes mellitus, chronic lung disease, and chronic kidney disease. The reason for the fatality of COVID-19 is viral sepsis. This host organ dysfunction is caused by a life-threatening, dysregulated inflammatory response (DIR) that initially has severe pulmonary complications 1, 2 . Therefore, there is generalized endothelial dysfunction leading to multiple organ dysfunction syndrome. Emerging evidence suggests that some patients may respond to COVID-19 with a disproportionate "cytokine storm," called secondary hemophagocytic lymphohistiocytosis (HLH) 3, 4 . This, however, is not merely a quantitative problem, and dysregulated inflammatory response, which is a functional problem not just a particular cytokine threshold is a better term to describe this phenomenon. This response must be associated with an organ dysfunction to be considered pathological 5 . Currently, although there are some promising data, there is insufficient evidence to support the recommendation for a specific, effective treatment for patients with COVID-19 6 . While numerous antiviral treatments are under investigation, their exclusive use may not be sufficient to control the aforementioned dysregulated inflammatory response. Therefore, there is growing interest in identifying alternatives with immunomodulatory action that can eliminate or reduce the formation of cytokines, thereby reducing both inflammatory tissue damage, particularly lung damage 7 , and mortality. An optimal blood purification technique could play a key role in this context 8 . The CONVEHY® protocol (Appendix B Online Supplements 1, 2, 3) was developed by the Hyperfiltration Research Group to control DIR and the cytokine storm through immunomodulation in patients with septic shock 9 . The DIR can be triggered by various events, including viral infections such as COVID-19, and can have different systemic effects on endothelial glycocalyx, such as vasodilation, fluid extravasation, and platelet micro-aggregation, in addition to kidney injury. Immunomodulation strategies that involve the elimination of inflammatory mediators should be considered in patients with poor response to treatments 10 . The oXiris® membrane 5 (BaxterTM, Illinois, USA) USA) is hollow fibre acrylonitrile and methanesulfonate (AN69ST) membrane with a surface treated with polyethyleneimine (PEI) and anchored heparin (AN69-ST-anchored heparin). It is a haemofilter that can eliminate interleukins (IL), tumour necrosis factor alpha (TNF-), migration inhibitory factor (MIF), interleukin-1 receptor antagonist (IL1-ra), high mobility group box 1 protein (HMGB-1), lipopolysaccharides (LPS), fibroblast growth factors (FGF21, FGF23), complement factors (C3a, C5a), and plasminogen activator inhibitor 1 (PAI-1), in addition to endotoxins. Its ability to remove molecules is related to its electrical charge, and therefore its isoelectric point. Although clinical experience in COVID-19 is limited [11] [12] [13] , in a single-centre, randomized, double-blind clinical trial, oXiris® proved effective in purifying blood and reducing the need for vasoactive agents in bacterial sepsis 14 . The Prismaflex system (BaxterTM, Illinois, USA) is used in conjunction with oXiris®. CONVEHY® uses a dose of citrate in a specific stage of the process, in this case specifically adapted to COVID-19. Adsorption capacity decreases over time due to membrane saturation, and membrane replacements are scheduled every six hours, at the discretion of the physician. The membrane can also be used solely for hemofiltration if only renal support is required at that time. The preliminary results of the use of the CONVEHY® protocol comparing outcomes before and after the inclusion of citrate have recently been published 9 . The SARS-CoV-2 receptor binding domain spike (S) binds to the ACE2 receptor through a remarkable network of hydrophilic interactions. Multiple bonds and two salt bridges can be found at the interface of this complex, with multiple tyrosine residues forming hydrogen-bonding interactions with the polar hydroxyl group 15, 16 . The aforementioned hydrophilic and hydrophobic characteristics of the SARS-CoV-2 virus allows it to adhere to the oXiris® membrane 17, 18 . Similar adsorption-based removal by lectin affinity plasmapheresis has been studied in other RNA viruses such as hepatitis C and Ebola virus 19 . The oXiris® membrane was given an emergency use authorization (EUA) by the United States Food and Drug Administration (FDA) to treat patients with confirmed COVID-19. This technique can be used to reduce pro-inflammatory cytokine levels in adult patients presenting any of the following conditions:  Early acute lung injury/early ARDS.  Serious disease  Life-threatening disease, defined as: -Respiratory insufficiency -Septic shock and/or -Multiple organ dysfunction or failure. Being an RNA (ribonucleic acid) virus, SARS-CoV-2 directly affects the immunomodulatory function of the mitochondria by modifying the mitochondrial antiviral signalling (MAV) receptors, thereby preventing interferon synthesis by the innate immune response. Other interleukins can also be modulated in the same way 20 . If the inflammatory response can be controlled in time, the immune system may be able to produce antibodies and overcome the infection 21 . The same strategy is used by our group in bacterial shock, although in this case we facilitate and allow time for antibiotics to act, and also determine whether the root cause can be controlled or an invasive treatment is needed. The use of high doses of citrate may be more beneficial that heparin with the oXiris® membrane due to: 1. Greater membrane efficiency -there is less activation of leukocytes and platelets and therefore less saturation 22 and greater durability at peak performance. 2. The PEI surface treatment is not completely saturated with the initial sodium heparin flushing solution -more PEI is available for adsorption; 3. The unpredictable negative effect of heparin in patients with septic shock and ischaemia-reperfusion injury, which could cause inflammation and microthrombi in the microcirculation 2. 3 and have disastrous effects on COVID-19 patients. Microthrombus involvement in the microcirculation has been described in autopsies of these patie nts 24 ; 4. Citrate, being a substrate of the respiratory cycle, can act at the mitochondrial level to improve metabolic alterations and keep respiratory complexes active, thus avoiding apoptosis 25 ; 5. Citrate can revive mitochondria and their respiratory and immunomodulatory function 20 . We believe that combining an effective adsorptive cleaning strategy with oXiris®, with controlled convection that helps eliminate inflammatory molecules, together with the effect of citrate on the mitochondria can result in faster and better recovery. This opinion contrasts with other solely renal support approaches (Fig. 1 ). In patients with COVID-19 timing the start of the technique can be decisive, and for now we have to rely on epidemiological and clinical risk factors for this purpose ( Fig. 2 and Table 1 ). CONVEHY® COVID-19 is intended as an early use protocol or rescue technique. It is designed to act as an anticyclone for the cytokine storm, thus restoring proper immune function. Its effectiveness could make it suitable for use in dialysis centres and critical care units, where it can treat as many patients as possible. The authors have not received any funding. 3 Resp. rate = Respiratory rate. rpm = respirations per minute. Heart rate = Heart rate. bpm = beats per minute. FiO 2 = fraction of inspired O 2 PaO 2 /FiO 2 = ratio of arterial oxygen partial pressure to fractional inspired oxygen. SpO 2 /FiO 2 = ratio of peripheral oxygen saturation to percentage of inspired oxygen. PaCO2 = partial pressure of carbon dioxide in arterial blood. CPK = creatine phosphokinase. mod-sev CKD = moderate-severe chronic kidney disease. CRP = C-reactive protein. DM HbA1c = glycated haemoglobin in patients with diabetes mellitus. LDH = lactate dehydrogenase. HT= arterial hypertension. HIV = human immunodeficiency virus. CD4 = CD4 lymphocytes or T4 lymphocytes. Specialist in Anaesthesiology and Resuscitation. Internal Medicine specialist. Head of the Post-surgical Resuscitation Unit. Anaesthesiology and Resuscitation Service. Hospital Universitario Puerta del Mar Specialist in Anaesthesiology and Resuscitation Specialist in Anaesthesiology and Resuscitation. Anaesthesiology and Resuscitation Service. Hospital Universitario Puerta del Mar Specialist in Anaesthesiology and Resuscitation. Anaesthesiology and Resuscitation Service. Hospital Universitario Puerta del Mar Specialist in Anaesthesiology and Resuscitation Specialist in Preventive Medicine. Preventive Medicine Service. Hospital Universitario Puerta del Mar Specialist in clinical analysis Anaesthesiology resident Anaesthesiology and Resuscitation Service. Hospital Universitario Puerta del Mar Anaesthesiology resident Anaesthesiology and Resuscitation Service. Hospital Universitario Puerta del Mar Specialist in Anaesthesiology and Resuscitation Specialist in Anaesthesiology and Resuscitation. Anaesthesiology and Resuscitation Service. Hospital Universitario Puerta del Mar Specialist in Anaesthesiology and Resuscitation. Anaesthesiology and Resuscitation Service. Hospital Universitario Puerta del Mar Specialist in Anaesthesiology and Resuscitation. Anaesthesiology and Resuscitation Service. Hospital Universitario Puerta del Mar Specialist in Anaesthesiology and Resuscitation. Anaesthesiology and Resuscitation Service. Hospital Universitario Puerta del Mar Specialist in Anaesthesiology and Resuscitation. Anaesthesiology and Resuscitation Service. Hospital Universitario Puerta del Mar Médico Interno Residente de Anestesiología. Servicio de Anestesiología y Reanimación. Hospital Universitario Puerta del Mar. AVDA. Ana de Viya 21 Médico Interno Residente de Anestesiología. Servicio de Anestesiología y Reanimación. Hospital Universitario Puerta del Mar. AVDA. Ana de Viya 21 Enfermero especialista en hemofiltración. Servicio de Anestesiología y Reanimación. Hospital Universitario Puerta del Mar. AVDA. Ana de Viya 21 Enfermero perfusionista. Servicio de Cirugía Cardiovascular Jefe de la unidad de cuidados críticos quirúrgicos. Hospital Clínico Universitario de Valladolid. Avda Jefe de la unidad de cuidados críticos quirúrgicos Hospital Universitario Carlos Haya. Avda. Carlos Hay 84. Málaga. 29010. España Profesor universitario. Especialista en Anestesiología y Reanimación. Jefe de servicio. Servicio de Anestesiología y Reanimación. Hospital Universitario Puerta del Mar. Avda. Ana de Viya 21 Especialista en Anestesiología y Reanimación. Servicio de Anestesiología y Reanimación. Hospital Universitario Puerta del Mar. AVDA. Ana de Viya 21 Dos terapias conocidas podrían ser efectivas como adyuvantes en el paciente crítico infectado por COVID-19. Revista Española de Anestesiología y Reanimación Recomendaciones prácticas para el manejo perioperatorio del paciente con sospecha o infección grave por coronavirus SARS-CoV-2. Revista Española de Anestesiología y Reanimación Adult haemophagocytic syndrome. The Lancet COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet Is a "Cytokine Storm" Relevant to COVID-19? Historically controlled comparison of glucocorticoids with or without tocilizumab versus supportive care only in patients with COVID-19-associated cytokine storm syndrome: results of the CHIC study. Annals of the Rheumatic Diseases Clinical features, ventilatory management, and outcome of ARDS caused by COVID-19 are similar to other causes of ARDS. Intensive Care Medicine Novel coronavirus disease (COVID-19) in hemodialysis patients: A report of two cases Estudio piloto sobre el uso de la hiperfiltración venosa continua para el manejo de pacientes en estado crítico con inflamación desregulada. Revista Española de Anestesiología y Reanimación Kidney involvement in COVID-19 and rationale for extracorporeal therapies Endotoxin and cytokine of the oXiris membrane in patients with septic shock: A randomized crossover double-blind study Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor Structural basis of receptor recognition by SARS-CoV-2 AN69 : Evolution of the World ' s First High Permeability Membrane Influence of the charge of low molecular weight proteins on their efficacy of filtration and/or adsorption on dialysis membranes with different intrinsic properties Extracorporeal virus elimination for the treatment of severe ebola virus disease -First experience with lectin affinity plasmapheresis Mitochondria are the powerhouses of immunity Can the Continuous Hemofiltration Control Ebola-induced Systemic Inflammatory Response Syndrome? Regional citrate anticoagulation reduces polymorphonuclear cell degranulation in critically ill patients treated with continuous venovenous hemofiltration Clinical review: anticoagulation for continuous renal replacement therapy--heparin or citrate? Critical care Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases Mitochondrial dysfunction during hypoxia/reoxygenation and its correction by anaerobic metabolism of citric acid cycle intermediates Figure 1 Combined immunomodulation strategy of the CONVEHY® protocol. oXiris® = trademark of the Acrylonitrile 69-Surface-Treated Heparin-Anchored membrane Co-authors of the CONVEHY GROUP® RESEARCH: Additional material to this article can be consulted in its electronic version available at doi: 10.1016 / j.redar.2020.08.001. References REFERENCIAS J o u r n a l P r e -p r o o f