Blood exchange transfusion with dexamethasone and Tocilizumab for management of hospitalized patients with sickle cell disease and severe <scp>COVID</scp>‐19: Preliminary evaluation of a novel algorithm
Authors: Gonzalo De Luna, Anoosha Habibi, Marie‐Hélène Odièvre, Henri Guillet, Vincent Guiraud, Pierre Cougoul, Benjamin Carpentier, Gylna Loko, Isabelle Guichard, Clément Ourghanlian, Jean Michel Pawlotsky, Matthieu Mahevas, Nicolas Limal, Marc Michel, Armand Mekontso‐Dessap, Jean‐Benoît Arlet, Pablo Bartolucci
Journal: American Journal of Hematology (2022)

Sickle cell disease (SCD) is a severe hemoglobin (Hb) disorder characterized by hemolytic anemia, recurrent painful vaso-occlusive events, and ischemia/reperfusion-driven inflammation. Acute chest syndrome (ACS) is a common and potentially life-threatening form of acute lung injury that can be triggered by infectious conditions. Coronavirus disease 2019 (COVID-19) infection represents a significant mortality risk for SCD patients, as death or required mechanical ventilation was reported for 5.6% of patients in the largest cohort of SCD patients hospitalized for COVID-19.1 In this cohort, ACS was described for 30% of patients. For SCD patients hospitalized with severe COVID-19 requiring supplemental oxygen, current therapeutic strategies may include corticosteroids, the interleukin-6 (IL-6) inhibitor Tocilizumab, or anticoagulant agents. Selection of the appropriate therapies may have a critical impact on patient outcome, due to the complex relationship between the drugs' mechanism of action and SCD pathophysiology. For instance, the use of corticosteroids in SCD patients should be approached with caution, as corticosteroids are associated with an increased risk of hospitalization for vaso-occlusive crises (VOC) or ACS.2 In contrast, Odièvre et al. reported dramatic improvement after Tocilizumab in COVID-19-related ACS in a pediatric SCD patient,3 as was also previously described in an adult SCD patient, suggesting that IL-6 could play an essential role in ACS pathophysiology. We propose here a treatment algorithm for SCD patients hospitalized with severe COVID-19. The aim of the algorithm is to minimize the worsening of SCD patients' clinical course related to corticosteroid therapy by proposing a prior blood exchange transfusion (BET); Tocilizumab is considered as alternative when transfusion is not recommended due to immunization against red blood cell (RBC) antigens. This algorithm was developed taking into consideration multiple aspects of SCD pathophysiology and of COVID-19 in SCD. Corticosteroid therapy in COVID-19 and the impact on SCD: Multiple randomized trials indicate that systemic corticosteroid therapy reduces mortality and improves clinical outcome in patients hospitalized with COVID-19 requiring supplemental oxygen. This is probably due to the mitigation of the COVID-19-induced systemic inflammatory response that can lead to lung injury and multisystem organ dysfunction. Systemic corticosteroid therapy is notoriously associated with an increased risk of SCD exacerbation and hospitalization for VOC or ACS. The SISTER study showed that corticosteroid exposure was significantly associated with hospitalization for VOC in an SCD French cohort2 with no COVID-19 infection. Corticosteroids have been previously shown to reduce ACS severity (especially duration of oxygen therapy and length of hospitalization) but are not considered a good treatment option, as they increase the risk of secondary VOC and early readmission. IL-6 inhibitors in COVID-19 and the impact on SCD: Results of published trials provide consistent evidence that the anti-IL-6 receptor monoclonal antibody, Tocilizumab, when administered with corticosteroids, offers a modest and somehow controversial clinical benefit in certain patients with COVID-19 who are severely ill, rapidly deteriorating, with increasing oxygen needs, and who have a significant inflammatory response. Outside of the COVID-19 context, sputum IL-6 level is a well-known biomarker of respiratory inflammation in SCD patients, and has been found increased at steady state in SCD children with a reported positive correlation between sputum IL-6 level and the number of ACS episodes. Increased levels of IL-6, IL-8, CCL2, and CCL3 have also been reported in the sputum of SCD children during ACS,4 possibly contributing to the recruitment of inflammatory cells in the lungs. Current therapeutic strategies for ACS are mainly supportive and do not target pulmonary and systemic inflammation, even though this is a major hallmark of the disease. Dramatic improvement of COVID-19-related ACS treated with Tocilizumab have been reported and appear safe and effective in SCD patients,3 in association with the usual treatment for severe ACS. Recently, a potential benefit of Tocilizumab in SCD patients during ACS, independently of COVID-19 infection, has been published.5 Indeed, new VOC therapeutic strategies targeting another IL (IL-1 beta) are currently being evaluated in a clinical trial, supporting the hypothesis of inflammasome activation in SCD. Anticoagulant agents in SCD and COVID-19: COVID-19 is an inflammatory condition at high risk for venous thromboembolism (VTE) as it has been associated with inflammation and a prothrombotic state accompanied by increases in fibrinogen and D-dimer. VTE, which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), has been recognized as a common complication of SCD. Arlet et al. show that Sickle Hemoglobin- C Disease (SC) genotype was the only independent factor associated with a higher risk of thrombosis.1 Transfusion in SCD: BET in SCD is performed in an acute manner to obtain immediate benefits, such as increased oxygen-carrying capacity and improved blood flow. It can also help prevent long-term complications by replacing rigid sickled erythrocytes with normal deformable cells and by suppressing the formation of sickled erythrocytes. Stroke and ACS are examples of acute organ damage that benefit from transfusion. BET aims to reduce the percentage of sickle hemoglobin (HbS) and attain <30% of HbS. This threshold is based on expert consensus rather than findings from randomized trials, and can be achieved by repeated manual exchange transfusions (RMET) or by erythrocytapheresis, a technique that removes sickled erythrocytes but maintains baseline hematocrit. In our experience, an HbS threshold of 30%–40% may be reached after two RMET cycles (using 2 RBC transfused units in each cycle) in a homozygous SCD patient with no previous transfusion. Delayed hemolytic transfusion reaction (DHTR) is a life-threatening complication of transfusions in SCD, which is induced by immunization against RBC antigens. Risk of DHTR can be assessed with a predictive score based on DHTR history, number of units previously transfused and immunization status before transfusion.6 Tozilizumab was infused after applying the proposed algorithm in all 11 patients represented by ACS related to COVID-19 in eight (73%) of them. BET was performed in 75% of ACS, and no needed in 25% of ACS due to dramatic improvement after Tocilizumab. Two patients (18%) died, all of them aged >40 years with ACS diagnosis, HbSC genotype in one and high comorbidity (kidney transplant) in second one. In Arlet et al. work, age was identified as an independent risk factor of severity, with an 8.3-fold increase in the risk of death or intubation for patients older than 40 when compared to the 20–40 age group; and SC genotype appeared as a particularly high-risk group, with a case fatality rate of 12%.1 In conclusion, severity of COVID-19 infection, ACS diagnosis and history of transfusion reactions must be taken into account when considering the use of corticosteroids for the management of severe COVID-19 pneumonia in SCD patients. Blood exchange transfusion must be considered prior to dexamethasone use in order to minimize the risk of VOC complications; IL-6 inhibitors should be proposed as an alternative to dexamethasone for patients at high risk for DHTR for whom transfusion must be avoided. Pr Bartolucci discloses the following: (a) consulting agreement for F. Hoffmann-La Roche,Addmedica, Novartis, Roche, Gbt, Bluebird, Emmaus, Hemanext, Agios; (b) Lecture fees from Novartis, Addmedica, Jazzpharma; (c) Steering committee for Novartis; (d) Research support from Addmedica, Foundation Fabre, Novartis, Bluebird; (e) cofounder of Innovhem. A single investigator (GDL) collected the data from patient interviews and chart reviews between March 13th, 2020 and January 17th, 2022. Clinical data were collected using a standardized form. All consecutive adult patients with SS-homozygous and S-heterozygous (S/β, SC) SCD (age >16 years) were followed at 3 SCD referral centers in France (Sickle Cell Referral Center, Department of Internal Medicine, Henri-Mondor University Hospital- UPEC, AP-HP, Créteil; Sickle Cell Center, University of the French West Indies, CHU de Martinique; and Armand-Trousseau Hospital, Service de Pédiatrie. Center for Sickle Cell Disease, Paris, France); and 3 others Hospitals in France: Institut Universitaire du Cancer Toulouse Oncopole, Médecine Interne, Toulouse, Hôpital Saint-Vincent de Paul, Hématologie, Lille and CHU Saint-Etienne, Médecine Interne, Saint Etienne A single investigator (GDL) collected the data from patient interviews and chart reviews between March 13th, 2020 and January 17th, 2022. Clinical data were collected using a standardized form. All consecutive adult patients with SS-homozygous and S-heterozygous (S/β, SC) SCD (age >16 years) were followed at 3 SCD referral centers in France (Sickle Cell Referral Center, Department of Internal Medicine, Henri-Mondor University Hospital- UPEC, AP-HP, Créteil; Sickle Cell Center, University of the French West Indies, CHU de Martinique; and Armand-Trousseau Hospital, Service de Pédiatrie. Center for Sickle Cell Disease, Paris, France); and 3 others Hospitals in France: Institut Universitaire du Cancer Toulouse Oncopole, Médecine Interne, Toulouse, Hôpital Saint-Vincent de Paul, Hématologie, Lille and CHU Saint-Etienne, Médecine Interne, Saint Etienne