Increased levels of GM-CSF and CXCL10 and low CD8+ memory stem T Cell count are markers of immunosenescence and severe COVID-19 in older people.

BACKGROUND: Ageing leads to altered immune responses, resulting in higher susceptibility to certain infections in the elderly. Immune ageing is a heterogeneous process also associated with inflammaging, a low-grade chronic inflammation. Altered cytotoxic T cell responses and cytokine storm have previously been described in severe COVID-19 cases, however the parameters responsible for such immune response failures are not well known. The aim of our study was to characterize CD8+ T cells and cytokines associated with ageing, in a cohort of patients aged over 70 years stratified by COVID-19 severity. RESULTS: One hundred and four patients were included in the study. We found that, in older people, COVID-19 severity was associated with (i) higher level of GM-CSF, CXCL10 (IP-10), VEGF, IL-1ß, CCL2 (MCP-1) and the neutrophil to lymphocyte ratio (NLR), (ii) increased terminally differentiated CD8+T cells, and (ii) decreased early precursors CD8+ T stem cell-like memory cells (TSCM) and CD27+CD28+. The cytokines mentioned above were found at higher concentrations in the COVID-19+ older cohort compared to a younger cohort in which they were not associated with disease severity. CONCLUSIONS: Our results highlight the particular importance of the myeloid lineage in COVID-19 severity among older people. As GM-CSF and CXCL10 were not associated with COVID-19 severity in younger patients, they may represent disease severity specific markers of ageing and should be considered in older people care.

Determinants of cognitive dysfunction in adults with sickle cell related stroke or suspected neurological morbidity.

The prognosis of sickle cell disease (SCD) in adults is determined primarily by damage to targeted organs such as the brain. Cognitive dysfunction in SCD is a common chronic neurological mani-festation but studies remain mostly descriptive in adults. The objective of this study was to better characterize the cognitive profile and the association between cognitive dysfunction and brain lesions. We included adult SCD patients referred for a neurological assessment. An adapted bat-tery of neuropsychological tests was used to assess cognitive deficits. Brain (white matter lesions or infarcts) or arterial (stenosis or occlusion) abnormalities were assessed using brain MRI/MRA and a cervical and transcranial Doppler ultrasound. The battery was completed in 96 patients. The cognitive profile was characterized by deficits in processing speed (58% (95% CI [48-68])), short-term memory (34% (95% CI [24-43])) and working memory (24% (95% CI [15-33])). Brain in-farcts were found in 56% of patients and intracranial vasculopathy in 49%. Twenty percent of pa-tients had no brain abnormalities. Processing speed dysfunction was associated with territorial in-farcts (OR 3.1, p=0.03) and education outside of France (OR 4.7, p=0.02). Short-term memory dysfunction was associated with territorial infarcts (OR 3.4, p=0.01) and a low educational level (OR 8.2, p=0.01). Working memory dysfunction was associated with a low educational level (OR 4.3, p=0.05) and vasculopathy (OR 3.7, p=0.03). Cognitive dysfunction appears to be a hallmark sign of SCD, particularly for adults with sickle cell related stroke or suspected neurological mor-bidity. Assessment of such dysfunction could be used in longitudinal follow up and clinical trials.

Assessment of fatigue in adult patients with sickle cell disease: Use of the functional assessment of chronic illness therapy-Fatigue (FACIT-fatigue) questionnaire.

Few studies have used validated scales to assess the intensity and determinants of fatigue, a major symptom of sickle cell disease (SCD). We aimed to assess the level of basal fatigue in adult patients with SCD, using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaire. We prospectively included 102 stable adult outpatients with SCD over 2 months, who answered the FACIT-Fatigue (ranging from 0 (worst imaginable fatigue) to 52 (no fatigue)) and reported on the intensity of fatigue and its impact on quality of life. The cut-off for significant fatigue was <34. The median [IQR] FACIT-Fatigue score was 29 [22-37], indicating moderate-to-severe fatigue. In a multivariate analysis, the FACIT-Fatigue score was significantly associated with female sex, high body mass index, high level of stress, poor sleep quality, and number of previous episodes of acute chest syndrome, but not with the genotype or the haemoglobin level. Most adult patients with SCD experience significant and sometimes intense fatigue; this is probably due to several factors, including disease activity. Fatigue should be evaluated systematically during consultations and in patient education programmes and as an end-point in therapeutic trials.

Impact of hospitalized vaso-occlusive crises in the previous calendar year on mortality and complications in adults with sickle cell disease: a French population-based study.

Background: Historically, sickle cell disease (SCD) patients experiencing frequent hospitalized vaso-occlusive crises (HVOC) have been associated with increased mortality, yet recent data reflecting the widespread use of hydroxyurea and advancements in disease management remain limited. Our study aims to assess the association between HVOC and mortality or severe complications in patients with SCD in this new treatment landscape. Methods: This was a retrospective observational cohort study using the French national health data system. Between 01-01-2012 and 12-31-2018, all SCD patients ≥16 years old (ICD-10 codes D57.0-2) were included and followed until 12-31-2018. HVOC was defined as a hospitalization of ≥1 night with primary diagnosis of SCD with crisis, following an emergency room visit. The association between HVOC and severe complications was assessed with a Cox proportional hazards model. Findings: In total, 8018 patients (56.6% females; 4538/8018) were included. The 2018 SCD standardized one-year period prevalence was 17.9 cases/100,000 person-years [17.4; 18.3]. The mean rate was 0.84 (1.88) HVOC/person-year. In 2018, 70% (5323/7605), 22% (1671/7605), and 8% (611/7605) of patients experienced 0, 1-2, or 3+ HVOCs, respectively. The median survival time between HVOCs was 415 days [386; 439]. Overall, 312 patients died (3.9%) with a mean age of 49.8 (19.4). Compared to patients without HVOC, the hazard ratios of death in patients with 1-2 or 3+ HVOCs the year prior to death were 1.67 [1.21; 2.30] and 3.70 [2.30; 5.93], respectively. Incidence of acute chest syndrome, pulmonary embolism, osteonecrosis, and sepsis increased with the HVOCs category, but not stroke. In 2018, 29.5% (180/611) of patients with 3+ HVOCs did not take hydroxyurea. Interpretation: Patients must be closely monitored during their hospitalizations to intensify treatment and check treatment compliance. Innovative therapies are also required. Funding: The study was funded by Novartis.

Ovarian tissue cryopreservation for fertility preservation before hematopoietic stem cell transplantation in patients with sickle cell disease: safety, ovarian function follow-up, and results of ovarian tissue transplantation.

PURPOSE: To describe the experience of performing ovarian tissue cryopreservation (OTC) before hematopoietic stem cell transplantation (HSCT), among girls/women with severe sickle cell disease (SCD)(SS or S/ß0-thalassemia) who are, besides the usual surgical risk, at risk of SCD-related complications during the fertility preservation procedure for improving their counseling and management. METHODS: This retrospective study included 75 patients (girls/women) with SCD who have had OTC before myeloablative conditioning regimen (MAC) for HSCT. Characteristics of patients and data on OTC, ovarian status follow-up, and results of ovarian tissue transplantation (OTT) were collected in medical records. RESULTS: At OTC, the median (IQR 25-75; range) age of the patients was 9.6 (6.9-14.1; 3.6-28.3) years, 56/75 were prepubertal, and no SCD or surgery-related complications occurred. The median follow-up post-HSCT was > 9 years. At the last follow-up, among prepubertal patients at HSCT, 26/56 were ≥ 15 years old and presented with a premature ovarian insufficiency (POI), except 2, including the patient who had received an OTT to induce puberty. Eight were 13-15 years old and presented for POI. The remaining 22 patients were under 13. Among the 19 patients who were menarche at HSCT, 2 died 6 months post-HSCT and we do not have ovarian function follow-up for the other 2 patients. All the remaining patients (n = 15) had POI. Five patients had OTT. All had a return of ovarian function. One patient gave birth to a healthy baby. CONCLUSION: OTC is a safe fertility preservation technique and could be offered before MAC independent of the patient's age.

Risk factors for thromboembolic events in patients hospitalized for COVID-19 pneumonia in a general ward and requiring treatment with oxygen.

PURPOSE: To assess risk factors for arterial and venous thromboses (AVT) in patients hospitalized in general wards for COVID-19 pneumonia and requiring oxygen therapy. METHODS: Our study was based on three randomized studies conducted as part of the CORIMUNO-19 platform in France between 27 March and 26 April 2020. Adult inpatients with COVID-19 pneumonia requiring at least 3 l/min of oxygen but not ventilation were randomized to receive standard care alone or standard care plus biologics. Patients were followed up for 3 months, and adverse events were documented. Risk factor for AVT and bleeding was identified by analyzing clinical, laboratory, and treatment data at baseline among the 315 patients with complete datasets. A Fine and Gray model was used to take account of competing events. RESULTS: During the 3-month follow-up period, 39 AVT occurred in 38 (10%) of the 388 patients: 26 deep vein thromboses and/or pulmonary embolisms in 25 (6%) patients, and 14 arterial thrombotic events in 13 (3%) patients. A history of diabetes at inclusion [sHR (95% CI) = 2.65 (1.19-5.91), P = .017] and the C-reactive protein (CRP) level (sHR = 1 [1-1.01], P = .049) were significantly associated with an elevated risk of thrombosis. Obesity was not associated with a higher risk of thrombosis (sHR = 1.01 [0.4-2.57], P = .98). The CRP level and diabetes were not risk factors for hemorrhage. CONCLUSION: Among patients hospitalized in general wards for COVID-19 pneumonia during the first wave of the epidemic, diabetes (but not obesity) and a high CRP level were risk factors for AVT. The use of higher doses of anticoagulant in these high-risk patients could be considered.

ATYPICAL FOVEAL AND PARAFOVEAL ABNORMALITIES IN SICKLE CELL DISEASE.

PURPOSE: The primary aim was to describe the patterns of paramacular involvement, not yet reported but that optical coherence tomography angiography can now detect in patients with sickle cell disease. The secondary aim was to search arguments concerning the physiopathogeny of paramacular involvement. METHODS: This institutional cohort retrospective study was conducted in a Referral Center for Ophthalmological Rare Diseases. Follow-up included an ophthalmologic examination with optical coherent tomography and optical coherent tomography angiography. RESULTS: One hundred and thirty-two patients with SCD were included. Typical sickle cell maculopathy was observed in temporal area in 84 eyes (40.0%) of SS patients and eight eyes (14.8%) of SC patients ( P < 0.001). Enlargement of the foveal avascular zone was observed in 10 eyes of eight SS patients. Two atypical parafoveal abnormalities were found in SS patients only. The first one consisted of macular thinning with normal vascularization in 15 eyes of 11 patients. The second atypical maculopathy was large areas of loss of vascularization without retinal thinning 10 eyes of six patients. Multivariate analysis did not show a statistically significant relation between the peripheral sickle retinopathy stage and the different type of sickle cell maculopathy ( P = 0.21). CONCLUSION: Those atypical sickle cell maculopathy may correspond to early forms preceding a typical sickle cell disease maculopathy (SCDM). This would point toward several physiopathogenic mechanisms. The first one included the existence of ischemia that can be related to anemia. Presence of retinal thinning without vascular involvement point out to a neurogenic mechanism.

A study of 28 pregnant women with sickle cell disease and COVID-19: elevated maternal and fetal morbidity rates.

Not available.

Relationship between paramacular thinning, cerebral vasculopathy, and hematological risk factors in sickle cell disease.

Purpose: To identify risk factors for sickle cell maculopathy due to hematological parameters (especially anemia and hemolysis) or cerebral vasculopathy. Methods: This retrospective study was conducted at a Referral Center. The follow-up included optical coherent tomography/optical coherent tomography angiography, neuro-radiological imaging, and a hematological assessment (hemoglobin, hemoglobin S level, reticulocytes, mean corpuscular volume, bilirubin, and lactate dehydrogenase). Results: Hundred and thirty-two sickle cell patients were included. Maculopathy was observed in 127 eyes of SS patients and 10 eyes of SC patients (p < 0.001), unrelated to peripheral retinopathy. Cerebral vasculopathy was more frequent in SS patients (p < 0.001) and was also associated with the presence of maculopathy (p = 0.049), and it was related to peripheral retinopathy (p < 0.001). All biological parameters significantly differed according to the genotype (p < 0.001) but not according to the presence of cerebral vasculopathy or maculopathy. In the multivariate analysis, reticulocytes and bilirubin were associated with the presence of cerebral vasculopathy and maculopathy. Conclusion: The data obtained were consistent with the role of anemia or hemolysis markers in cerebral vasculopathy and macular involvement. As a trend of hemolysis appears to be a risk factor for these complications, this validates the use of preventive plasmapheresis in these patients.

Transbronchial cryobiopsy proven amyloid diffuse cystic lung disease complicating a transthyretin mutated (ATTRm) amyloidosis: a case report.

We present a case report of transbronchial cryobiopsy proven diffuse amyloid cystic lung disease complicating a homozygous Val122Ile (V122I) transthyretin mutated amyloidosis (ATTRm). To the best of our knowledge, this is the first case in the literature reporting such pulmonary lesions in ATTRm amyloidosis, and notably diagnosed through cryobiopsy. A 51-year-old man from Mali with a past medical history of bilateral carpal tunnel syndrome presented erectile dysfunction, asthenia and worsening dyspnoea over the past year. He presented signs of cardiac failure; histological and radiological investigations diagnosed cardiac amyloidosis. He was found homozygote for the V122I mutation in transthyretin. A diffuse cystic lung disease (DCLD) was noted on computed tomography (CT) scan. We performed a transbronchial pulmonary cryobiopsy that revealed histological transthyretin amyloid deposits. This case report illustrates the safety and usefulness of cryobiopsy in the setting of DCLD and extends ATTRm amyloidosis as a possible cause of DCLD.

[Epidemiology of sickle cell disease in France and in the world]. / Épidémiologie de la drépanocytose en France et dans le monde.

EPIDEMIOLOGY OF SICKLE CELL DISEASE IN FRANCE AND IN THE WORLD. In a few decades, sickle cell disease has become the leading rare disease in France, with nearly 30,000 patients. It is the country in Europe where the most patients live. For historical reasons of immigration, half of these French patients live in the Paris area. The number of births of affected children increases every year, which explains the recurrent and increasing hospitalizations for vaso-occlusive crises, impacting the care system. Sub-Saharan African countries, along with India, are the countries most affected by the disease with an incidence of up to 1% of births. While infant mortality has become rare in industrialized countries, it is major in Africa where more than half of the children will not reach the age of 10.

ÉPIDÉMIOLOGIE DE LA DRÉPANOCYTOSE EN FRANCE ET DANS LE MONDE. En quelques dizaines d'années, la drépanocytose est devenue la première des maladies rares en France, avec près de 30 000 patients. C'est le pays d'Europe où vivent le plus de patients. Pour des raisons historiques d'immigration, la moitié de ces patients français vivent en Île-de-France. Le nombre de naissances d'enfants atteints augmente chaque année, ce qui explique des hospitalisations récurrentes et croissantes pour crises vaso-occlusives, impactant le système de soin mal préparé. Les pays d'Afrique subsaharienne sont, avec l'Inde, les pays les plus touchés par la maladie, avec une incidence allant jusqu'à 1 % des naissances. Alors que la mortalité infantile est devenue rare dans les pays industrialisés, elle est majeure en Afrique, où plus de la moitié des enfants n'atteindront pas l'âge de 10 ans.