Drepadom - Establishment of Home Care Services and Hospitalizations for Sickle Cell Disease Patients As Standard Care Since the Covid-19 Pandemic

INTRODUCTION Vaso-occlusive crisis (VOC), hallmark of sickle-cell disease (SCD), is the first cause of patients' emergency room (ER) admissions and hospitalizations. Acute chest syndrome (ACS) is a life-threatening complication that can occur during VOC and prolong hospitalization and is one of the main causes of death in SCD patients. The PRESEV score, established by team members and colleagues, assesses the risk of developing ACS (Bartolucci et al., 2016). In addition, the score has been validated by an international multicenter study, involving 13 centers, distributed in five different countries (PRESEV 2 - ASH 2020). Throughout the first wave of the Covid-19 pandemic, VOC management for SCD patients was a major concern. Our sickle cell referral center set up a hotline to monitor patients suffering from VOC daily, and organized the deployment of home-care services when required. The success of this system during the first wave of the pandemic led to the establishment of DREPADOM, a home-care and hospitalization protocol for VOC management in patients who are at a low risk of developing ACS, as standard care. DESCRIPTION OF SETTING Patients eligible for DREPADOM are patients that arrive at the ER for a VOC with a low PRESEV score, meaning low risk of developing ACS;or patients that are discharged early following hospitalization for VOC. After physical examination and calculation of the PRESEV score, DREPADOM home hospitalization is systematically offered to patients arriving to the ER with a PRESEV score ≤ 5. If the patient agrees, the DREPADOM nurse coordinator then acts as a link between the pharmacist, the oxygen supplier, the homecare provider, and the DREPADOM medical platform to activate the home hospitalization protocol. This entails the delivery of oxygen supply at the patient's house, dispatch of a medical prescription of opioids and parenteral treatments, twice/thrice-daily visits from homecare nurses, and an on-call SCD expert. DREPADOM relies on a system of daily telephone calls with three levels of expertise and warning and a decision-making algorithm. This is supervised by SCD experts, who arbitrate according to the evolution of the situation (stopping the follow-up, continuing the follow-up as an outpatient, hospitalization) (Fig.1). Furthermore, nurses enter patient vitals in real-time during their daily visits on a dedicated online platform (Link4Life) that contains an integrated automatic alert system. Additionally, a daily phone update between the DREPADOM coordination and the homecare provider's coordination concerning status and evolution of the patient's global condition takes place. RESULTS Over a 6-month period, 39 patients were included in the DREPADOM home hospitalization protocol, 3 of which were included multiple times for a total of 42 inclusions. Mean age was 40 years old [±9], sex ratio was 14/25 (male/female), ER vs early discharge ratio was 21/22, and mean homecare follow-up was 3 days (±1) for both, patients arriving from the ER and early discharge patients. Throughout the third wave of the pandemic, when hospital saturation was a major concern, patients with PRESEV scores 5 ≤ 11 were also offered DREPADOM. Three patients were hospitalized (7%): one for an ACS, who was included during the 3 rd wave of the pandemic with a PRESEV score of 8;one for pyelonephritis unrelated to the VOC;and one for difficulties with venous access. No death was reported. PERSPECTIVES Preliminary satisfaction surveys show a great enthusiasm for DREPADOM, partly due to the high standard of care received, but also due to the shorter length of hospitalization. In fact, median hospital stay for VOC is 4 [3-7] days (Bartolucci, 2016) whereas median homecare follow-up was 3 [1-6] days. [Formula presented] Disclosures: Bartolucci: Hemanext: Consultancy;Jazz Pharma: Other: Lecture fees;AGIOS: Consultancy;F. Hoffmann-La Roche Ltd: Consultancy;Emmaus: Consultancy;GBT: Consultancy;INNOVHEM: Other: Co-founder;Bluebird: Consultancy, Research Funding;Novartis: Consultancy, Membership on an entity's B ard of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding;Addmedica: Consultancy, Other: Lecture fees, Research Funding;Fabre Foundation: Research Funding.

Causes and Circumstances of Death: Analysis in 266 Sickle Cell Adult Patients

Introduction Sickle cell disease is a genetic disease with acute and chronic complications. Pediatric mortality has decreased in recent decades with the introduction of systematic antibiotic therapy, preventive management of cerebral vasculopathy and therapeutic education of families. However, in the absence of cohort follow-up at birth, life expectancy, which is a different concept from age at death, cannot be assessed. In this retrospective, monocentric study, we describe causes and circumstances of death, acute chronic complications, long-term treatments and baseline biology of these patients. It seems important to analyze the risks of morbidity and mortality in order to decide on the necessary preventive measures. Material and method: Records of patients deceased between 2000 and 2020, from the national referral center (Henri Mondor Hospital), were retrospectively reviewed. The referral center follows 3500 patients. All deaths reported to the hospital, by families, other hospitals and health professionals were retrieved from computerized records. Deaths published by the INSEE (National Institute of Statistical and Economical study) from 2000 to December 2020 were accessible and compared with our databases to identify all our deceased patients. All patients with a medical record in our center were included for the study. Patients who had never visited our center were excluded. Results: During this period 226 patients including 128 women and 138 men are recorded. Genotypes for these patients were 204(76%) SS, 41 (15%) SC, 14(5%) Sβ°thalassemia and 7 (2%) Sβ+thalassemia. The median age at death was 41 years with an IQR [32-51]. 186 (70%) patients were hospitalized, 129 (70%) of whom were admitted to intensive care. 36 (13%) patients died at home, including 15 with opioid addiction and 5 patients with psychiatric pathology, and 4 patients on dialysis. This information was not available for 44 (16%) patients. The causes of death were vaso-occlusive complications with multivisceral failure in 44 cases, 42 sepsis, among which there were 11 renal failures, 9 of which were dialyzed. 5 patients died of COVID 19. Cerebral hemorrhage and neurological accident occurred in 22 cases, 4 of which were known to have macrovasculopathy. 25 patients died of a direct complication of renal failure, of which 17 were dialysed, 8 pre-dialysed and 3 transplanted. Acute liver failure in 16 cases, 10 precapillary pulmonary hypertension, 14 DHTR, 10 end-stage heart failure were noted. Two road accidents, 2 suicides, 1 dementia are repoted. For 51 cases, there was no information on the cause or circumstance of death. The causes of death according to genotype is on Table 1. Concerning the chronic complications, 94/266 (35%) patients had significant chronic organ damage. Sixteen patients had required renal or liver transplantation in their history. End-stage organ damage was frequent, 42 had end-stage renal failure, 21 had major liver failure, of which five were transplanted and 16 were awaiting transplantation. Twenty-one patients had known heart failure, 10 of which were associated with end-stage renal disease. Ten patients were followed for significant precapillary pulmonary hypertension. Transfusion difficulties due to a history of DHTR were found for 33 patients. Fourteen patients had an opioid addiction. Nine patients were pregnant and nine had received corticosteroids. Discussion: Causes of death have changed and chronic organ failure is the leading cause of death, especially in patients with kidney, liver and heart disease. This study does not calculate life expectancy, but there was an increase in age at death of about 1/4 of the patients who were between 51 and 81 years old.The management of sickle cell disease has progressed in recent years and new therapies are being proposed. Prevention of the development of these complications is one of the new challenges, especially for renal disease, which is associated with premature mortality. DHTR and cerebral hemorrhage, Covid-19 are new entities and DHTR was probably underdiagnosed in p evious publications. Pregnancy remains a period at risk, for which surveillance should be reinforced. The analysis is ongoing and correlations are currently being investigated between different parameters to find risk factors for mortality. [Formula presented] Disclosures: Habibi: Novartis: Consultancy, Honoraria;bluebird bio: Consultancy, Honoraria, Research Funding. Audard: Addmedica: Consultancy. Michel: Novartis: Consultancy;Amgen: Consultancy;Rigel: Honoraria;Alexion: Honoraria;UCB: Honoraria;Argenx: Honoraria. Galactéros: Addmedica: Membership on an entity's Board of Directors or advisory committees. Bartolucci: INNOVHEM: Other: Co-founder;Bluebird: Consultancy, Research Funding;F. Hoffmann-La Roche Ltd: Consultancy;GBT: Consultancy;Jazz Pharma: Other: Lecture fees;AGIOS: Consultancy;Hemanext: Consultancy;Emmaus: Consultancy;Fabre Foundation: Research Funding;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding;Addmedica: Consultancy, Other: Lecture fees, Research Funding.

Facteurs de risque de COVID-19 sévère chez des patients drépanocytaires hospitalisés : étude nationale Française chez 319 patients

Introduction Les patients drépanocytaires sont à risque de surinfection bactérienne du fait de l’asplénie fonctionnelle induite par la maladie. Leur fragilité vis-à-vis d’une infection virale n’a jamais bien été établie si ce n’est que celle-ci augmente le risque de crise vaso-occlusive (CVO) et donc d’hospitalisation. Les patients drépanocytaires ont très tôt été considérés comme personnes “fragiles” vis-à-vis de la COVID-19 mais cela reste controversé et les facteurs de gravité dans cette population sont mal connus. Nous avons voulu identifier les facteurs de risque associés à des formes sévères de COVID-19 dans une cohorte de patients drépanocytaires infectés par le SARS-Cov2 et hospitalisés. Matériels et méthodes Cohorte prospective, multicentrique et observationnelle Française incluant des patients drépanocytaires hospitalisés avec une infection SARS-CoV-2 confirmée (par test RT-PCR sur écouvillon naso-pharyngé) entre mars 2020 et mai 2021. Les données cliniques et le devenir durant l’hospitalisation ont été recueillis. Un modèle de régression logistique multivarié a été utilisé pour identifier les facteurs associés aux formes sévères de COVID-19 définies par le recours à une ventilation mécanique ou un décès intra-hospitalier. Nous avons effectué des comparaisons en fonction des génotypes de drépanocytose. Résultats 319 patients drépanocytaires, d’âge moyen 27,4 ans (de 2 mois à 85,5 ans), ont été hospitalisés concomitamment à la découverte d’une infection par le SARS-CoV-2. Sept (2,2 %) sont décédés, uniquement des adultes. Chez les adultes, les patients âgés de plus de 40 ans (n=59) présentaient un risque 8,3 fois plus élevé [IC 95 % 2,6–31,2] de décès ou d’intubation par rapport aux patients âgés de 20 à 40 ans (n=153) (P<0,001). Aucun patient de moins de 20 ans n’a été intubé. Lorsque l’on stratifie en fonction de la présence ou non d’une CVO (67 % des patients) ou d’un syndrome thoracique aigu (STA 30,5 %), la survenue d’une intubation ou d’un décès était plus faible chez les patients pour lesquels une CVO ou un STA était présents (aOR : 0,24 [0,06–0,92] ;p=0,037 pour la CVO ;aOR : 0,71 [0,08–6,16] ;p=0,760 pour le STA). En analyse multivariée, le génotype SC (n=33 patients) était indépendamment associé à un risque plus élevé de nécessiter une ventilation mécanique ou de mourir (24,2 % contre 3,6 % pour les patients SS/Sβ0, P<0,001 ;aOR : 6,99 [IC 95 % 1,42–34,5]). L’âge était l’autre facteur significatif. Par rapport aux patients SS/Sβ0, les patients SC présentaient également un risque plus élevé de survenue de thromboses (28,1 % vs 6,3 % pour les SS/Sβ0, P<0,001 ;aOR : 5,86 [IC 95 % 1,59–21,59]). Dans le sous-groupe SS/Sβ0 (n=276), les facteurs associés à la ventilation mécanique ou au décès étaient l’âge, l’indice de masse corporelle, l’hypertension artérielle, le diabète et l’utilisation de médicaments immunosuppresseurs. L’âge plus élevé était le principal facteur de risque de ventilation mécanique ou de décès chez les patients SC. Conclusion Nos résultats montrent que les patients drépanocytaires SC hospitalisés avec la COVID-19 ont un risque beaucoup plus élevé d’évolution sévère, associé à davantage de complications thrombo-emboliques. Ces résultats sont surprenant tant ce génotype (20 % des drépanocytaires en France) est considéré comme le moins sévère, associé à une espérance de vie meilleure que les homozygotes. Ces patients SC devraient, avec l’ensemble des drépanocytaires de plus de 40 ans, constituer un groupe de patients ultraprioritaires pour la vaccination, notamment dans des pays où la vaccination est peu accessible. L’utilisation d’une anticoagulation curative chez un patient SC hospitalisé avec la COVID est une question ouverte par ce travail.

Caractéristiques des patients drépanocytaires infectés par le SARS-CoV-2 en fonction de leur prise en charge ambulatoire ou en hospitalisation : étude nationale chez 536 patients

Introduction Les patients drépanocytaires ont très tôt été considérés comme personnes “fragiles” vis-à-vis de la COVID-19 car, indépendamment du risque propre de l’infection, il est bien établi que toute infection peut déclencher une crise vaso-occlusive (CVO). Il y a cependant peu d’études descriptives sur larges cohortes décrivant les caractéristiques des patients drépanocytaires avec COVID-19. Nous avons voulu comparer les caractéristiques des patients drépanocytaires infectés par le SARS-Cov2 suivant qu’ils aient été ou non hospitalisés afin d’établir un profil des patients ayant nécessité une hospitalisation. Matériels et méthodes Étude de cohorte prospective, multicentrique et observationnelle Française. Dès le 13 mars 2020, nous avons établi en France grâce au réseau des centres de référence/compétence et de la filière de santé MCGRE (pédiatrie et médecine adulte), un appel à déclaration de toutes infections à SARS-CoV-2 consécutives confirmées par test RT-PCR sur écouvillon naso-pharyngé. Les caractéristiques cliniques simples concernant la drépanocytose et son traitement et les signes cliniques de l’infection ont été recueillis sur une fiche de recueil standardisée. Un modèle univarié a été utilisé pour comparer les caractéristiques des patients, par génotypes de drépanocytose et selon qu’ils aient été pris en charge en ambulatoire ou hospitalisés (passage au minimum d’une nuit aux urgences). Résultats 536 patients drépanocytaires infectés par le SARS-CoV-2 ont été inclus : 319 patients hospitalisés et 217 non hospitalisés. Il s’agissait de 431 drépanocytaires de génotypes S/S ou S/b0-thalassémie (âge moyen 27±12,7 ans), 82 de génotype SC (âge moyen de 33,6±15 ans) et 23 de génotype S/b±halassémie (29,7±15,4 ans). Nous détaillons dans ce résumé les données concernant les patients majoritaires, de génotype S/S ou S/b0-thalassémie. Chez ces patients, l’âge moyen, le sexe, l’index de masse corporelle, les antécédents de syndrome thoracique aigu (STA), d’HTA ou de diabète, le traitement par hydroxyurée ou immunosuppresseurs étaient identiques entre patients infectés hospitalisés et infectés ambulatoires. Les patients hospitalisés avaient très nettement plus de crises vaso-occlusives osseuses (67 % vs. 13 %, P<0,001) et étaient moins transfusés dans les 60jours avant la PCR (10,1 % vs. 24,5 %, P=0,01). Ils étaient plus anémiques que les patients ambulatoires (-0,8g/dl d’hémoglobine en médiane, P=0,003). Parmi les symptômes de l’infection, les patients hospitalisés avaient plus souvent de la fièvre (55 % vs. 35 %, P<0,001) et de la dyspnée (19,2 % vs 6,4 %, p<0,001), mais beaucoup moins de symptômes ORL (incluant rhinorrhée et/ou agueusie et/ou anosmie) (11,8 vs. 36,9 %, p<0,001). Chez les patients SC les mêmes tendances étaient observées même si elles n’étaient pas toujours significatives du fait d’un effectif plus faible (33 hospitalisés vs. 49 non hospitalisés). C’est le cas des CVO osseuses présentes chez 57,6 % des SC hospitalisés vs 12,8 % des non hospitalisés (P<0,001) et de la dyspnée (24,2 % vs 6,8 %, p<0,045). Conclusion Les CVO osseuses expliquent l’hospitalisation d’un grand nombre d’infections COVID-19 chez le patient drépanocytaire. La transfusion dans les 2 mois pourrait prévenir ces CVO « viro-induites » et ces hospitalisations alors que l’ hydroxyurée ne semble pas être un facteur protecteur. La présence de signes ORL est associée à moins d’hospitalisations, comme l’ont montré d’autres études en population générale avec COVID-19. Cela pourrait être un élément de « tri » des malades en cas de forte affluence épidémique, en plus des éléments de gravité classiques de la COVID-19 ou de la CVO.

Validation of a Predictive Score of Acute Chest Syndrome (presev-2 study) in Adults

Introduction Vaso-Occlusive Crisis (VOC), the most common manifestation of sickle cell disease (SCD), is the first cause of death when complicated by an acute chest syndrome (ACS). We previously developed a predictive score for the occurrence of ACS in SCD patients admitted at hospital for a VOC episode (Bartolucci et al., 2016). Two hundred and fifty patients with severe VOC requiring hospitalization were included in the PRESEV I study and 19% developed a secondary ACS within days post-admission (median [IQR] : 3 [2.3]). A multivariate analysis of these data established a predictive score of secondary ACS, with a negative predictive value of 98,9% for the low-level risk. Variables for calculation of the score were: reticulocytes and leucocytes counts, hemoglobin and categorical pain score (spine -pelvis). Interestingly enough, Hydroxyurea treatment did not have any impact on the score. Our goal was to validate this score in a multicenter international study, as it could represent a useful tool for physicians, for improving VOC management, but also be of use for therapeutic trials. Herein, we present results for adults. Methods This international, multicenter, prospective, observational study was performed in thirteen centres, over two continents (Africa and Europe) and five countries (Mali, Togo, England, Belgium and France). Homozygous SCD patients, both adults and children (>2 years), were included, with severe VOC requiring admission at the emergency unit. Severe VOC was defined as pain or tenderness affecting at least one part of the body (e.g. limbs, ribs, sternum, head, spine and/or pelvis) requiring opioids (level 3) and not attributable to other causes. The primary outcome measure was the occurrence of an ACS, defined as an auscultatory abnormality (crepitation or bronchial breathing), or the association of a new radiologic infiltrate and chest pain or decreased breath sounds. Secondary outcome measures were hospital length of stay, morphine consumption, transfusion, hospitalization in intensive care unit and mortality. The following parameters were recorded: temperature, blood pressure, oxygen saturation, respiratory frequency, categorical pain score. Pulmonary auscultation was performed at least once a day by a physician, every day, for the length of stay. The auscultatory abnormality, defined as crepitation, bronchial breathing or decreased breath sounds, was confirmed by a second physician. If a patient was discharged before day 5, follow-up with a phone call and/or a visit, 3 to 7 days after discharge were performed, to prevent complications or ACS. Results Three hundred and seventy-two adult patients with a severe VOC requiring hospitalization were included. Mean age was 29 (±8) years old, sex ratio (female/male) was 1.2. A hundred and ninety-one patients came from Europe and 181 from Africa. Out of the 372 patients, 68 (18.3%) further developed a secondary ACS. Mean day of ACS episode was 3.3 (±1.37). Among the 304 patients who did not develop an ACS episode (81.7%), 41 had a low risk score of developing a secondary ACS (predictive score ≤ 5). Among the 68 patients who developed a secondary ACS, 43 had a high-risk score (≥ 11). Results are shown in table 1. Three deaths were reported, all on African continent (ACS, anemia and end-stage nephropathy). Discussion and Conclusion Our multicenter international study has allowed confirmation of the incidence of patients developing a secondary ACS during a VOC. This study confirms that the PRESEV score could indeed represent a useful tool for physicians, most especially within emergency structures, by identifying patients with a low risk of further developing an ACS with a good NPV and thus, allowing a better management of SCD patients experiencing a VOC. The PRESEV score was successfully put to practice during the Covid-19 pandemic at the referral SCD center of Henri Mondor hospital and identified “low-risk” patients, who benefited from homecare services (DREPADOM). As such, the PRESEV score could represent a significant help when one considers t e shortness of bed availabilities in certain circumstances (pandemics, hospital settings in resource-limited countries, etc…). Finally, the identification of “high-risk” patients could also become useful for improving the feasibility of clinical trials for the prevention of ACS. [Formula presented] Disclosures: Arlet: Novartis: Consultancy, Honoraria. Bartolucci: Novartis: Research Funding;Emmaus: Consultancy;Addmedica: Research Funding;Fabre Foundation: Research Funding;ADDMEDICA: Consultancy;HEMANEXT: Consultancy;AGIOS: Consultancy;Roche: Consultancy;Bluebird: Consultancy;Bluebird: Research Funding;Innovhem: Other;GBT: Consultancy;Novartis: Consultancy.