Persistent COVID-19: a case report of an immunocompromised patient and a literature review.

Introduction Immunocompromised patients can show prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and persistent symptoms, which is called persistent COVID-19. Case presentation We report a case of an immunocompromised patient who was treated for mantle cell lymphoma and was suffering from B-cell depletion. The patient developed persistent COVID-19, which was confirmed by real-time polymerase chain reaction (RT-PCR) tests in only sputum and bronchoalveolar fluid which remained positive for at least 112 days. The patient was successfully treated with SARS-CoV-2 convalescent plasma. Conclusion It could be of interest to investigate the RT-PCR results of SARS-CoV-2 in sputum/bronchoalveolar lavage samples from immunocompromised patients with unexplained pneumonia.

Factors associated with dexamethasone efficacy in COVID-19. A retrospective investigative cohort study.

Dexamethasone has demonstrated efficacy in reducing mortality in COVID-19. However, its practical use is badly defined. We aimed to investigate factors associated with dexamethasone efficacy in real life. Our retrospective study was conducted in two university hospitals between September and November 2020 and included all the consecutive hospitalized patients with a laboratory-confirmed SARS-CoV-2 infection assessed by RT-PCR, treated with intravenous dexamethasone (6 mg/day). Among 111 patients, 10.6% necessitated a transfer into the intensive care unit (ICU) and the 28-day mortality rate was 17.1%. The 28-day mortality rate was significantly lower in patients who demonstrated improvement at 48 h (hazard ratio [HR]: 0.17, 95% confidence interval [CI]: 0.04-0.78, p = 0.02) and 96 h (HR: 0.07, 95% CI: 0.02-0.31, p = 0.0005) after dexamethasone initiation. Apart from well-known risk factors (age, hypertension, active cancer, severe lesions on chest computed tomography [CT] scan), we found that a high viral load in nasopharyngeal swab (Cycle threshold <30) at dexamethasone initiation was associated with higher 28-day mortality (66.6% vs. 36.7%, p = 0.03). Patients who did not receive antibiotics at dexamethasone initiation had a higher rate of transfer into the ICU (55.6% vs. 23.5%, p = 0.045) with a trend towards higher mortality in case of severe or critical lesions on CT scan (75.0% vs. 25.0%, p = 0.053). Patients who did not improve within 2-4 days after steroid initiation have a bad prognosis and should receive additional anti-inflammatory drugs. Our data suggest better efficacy of dexamethasone in patients with a low or negative viral load, receiving broad-spectrum antibiotics.

Anti-NuMA antibodies: clinical associations and significance in patients with primary Sjögren's syndrome or systemic lupus erythematosus.

OBJECTIVE: To determine the clinical significance of anti-nuclear mitotic apparatus (NuMA) antibodies (AC-26 or AC-25) in patients with primary Sjögren's syndrome (pSS) and SLE. METHODS: Between 2013 and 2018, clinical and immunological features of pSS and SLE patients with anti-NuMA antibodies were compared with anti-NuMA antibodies-negative pSS and SLE cohorts. RESULTS: Among 31 284 sera positive for antinuclear antibodies, 90 patients (0.29%) had anti-AC-26 (anti-NuMA1) and AC-25 (anti-HsEg5) antibodies (73.3% and 26.7%, respectively). Autoimmune diseases, mainly consisting in pSS (28.9%) and SLE (21.1%), were found in 67.8%. Anti-NuMA antibodies represented the unique ANA in 60% and 50% of patients with pSS and SLE patients, respectively. Compared with 137 anti-NuMA-negative pSS patients, 20 anti-NuMA-positive pSS presented with less frequent ocular sicca syndrome (70.0% vs 89.1%, P=0.031), dryness complications (15.0% vs 39.4%, P=0.045), or detectable anti-SSa and/or anti-SSb antibodies (40.0% vs 66.4%, P=0.027). Compared with 80 anti-NuMA-negative SLE patients, 14 anti-NuMA-positive SLE patients had no lupus nephritis (0.0% vs 28.8%, P=0.049), less frequent dsDNA antibodies (42.9% vs 75.0%, P=0.025) and complement consumption (21.4% vs 53.8%, P=0.040). Anti-NuMA-positive pSS and SLE patients less frequently required treatments compared with anti-NuMA-negative patients. CONCLUSION: Although rare, anti-NuMA antibodies are mainly associated with pSS and SLE and may be useful for diagnosis when other auto-antibodies are negative. PSS and SLE patients with anti-NuMA antibodies have less severe clinical and biological profiles, suggesting that anti-NuMA antibodies may constitute a good prognosis marker in both autoimmune diseases.

Clinical characteristics and outcomes of patients with haematologic malignancies and COVID-19 suggest that prolonged SARS-CoV-2 carriage is an important issue.

Specificities of COVID-19 disease course in patients with haematologic malignancies are still poorly studied. So, we aimed to compare patients with haematologic malignancies to patients without malignancies, matched by sex and age and hospitalised for COVID-19 at the same time and in the same centre. Among 25 patients with haematologic malignancies, we found that mortality (40% versus 4%, p < 0.01), number of days with RT-PCR positivity (21.2 ± 15.9 days [range, 3-57] versus 7.4 ± 5.6 days [range, 1-24], p < 0.01), maximal viral load (mean minimal Ct, 17.2 ± 5.2 [range, 10-30] versus 26.5 ± 5.1 [range, 15-33], p < 0.0001) and the delay between symptom onset and clinical worsening (mean time duration between symptom onset and first day of maximum requirement in inspired oxygen fraction, 14.3 ± 10.7 days versus 9.6 ± 3.7 days, p = 0.0485) were higher than in other patients. COVID-19 course in patients with haematologic malignancies has a delayed onset and is more severe with a higher mortality, and patients may be considered as super-spreaders. Clinicians and intensivists need to be trained to understand the specificity of COVID-19 courses in patients with haematological malignancies.

High Serum Vitamin B12 Levels Associated with C-Reactive Protein in Older Patients with Cancer.

BACKGROUND: A Comprehensive Geriatric Assessment (CGA) has been proposed to assess prognosis and to adapt oncological care in older patients with cancer. However, few biological markers are incorporated in the CGA. METHODS: This comparative study on older patients with cancer was realized before final therapeutic decision and during a CGA that included biological markers. Our objective study was to know if the serum vitamin B12-C-reactive protein index (BCI) can help to estimate early death and unplanned hospitalization. Associations between BCI and unplanned hospitalization or mortality were analyzed using ordered multivariate logistic regression. FINDINGS: We included 621 older cancer adults in outpatient care with a median age of 81 years (range, 70-98 years) from September 2015 to May 2018. In this study, 5.6% of patients died within 3 months, 8.8% had unplanned hospitalization within 1 month, and 11.4% had unplanned hospitalization within 3 months. Hypercobalaminemia was present in 83 patients (13.4%), and 34 patients (5.5%) had BCI >40,000. According to the multivariate analysis, BCI was a prognostic factor of mortality within 3 months and unplanned hospitalizations at 1 and 3 months. Impaired activities of daily living (ADL) and palliative care were also risk factors for mortality within 3 months. Impaired instrumental ADL, low albumin level, and palliative care were risk factors for unplanned hospitalization at 1 month. INTERPRETATION: BCI could be routinely added to the CGA process, as part of a pretreatment workup, in order to assess more precisely the frailties and to adapt oncological care in older patients treated for cancer. IMPLICATIONS FOR PRACTICE: Aging comes with an increase of frailties and comorbidities. To identify frailties in older patients with cancer, this study used a Comprehensive Geriatric Assessment, which allowed for the adaptation of each treatment plan in accordance with the individual needs of the patients. However, biological characteristics were not included in this assessment. This study showed that hypercobalaminemia and vitamin B12 -C-reactive protein index may be potential markers for cancer with poor prognosis, particularly in the older population. These biological markers can be used in geriatric oncology and general medicine.

Efficacy and safety of autologous stem cell transplantation after induction therapy with lenalidomide, bortezomib, and dexamethasone.

OBJECTIVES: Recently, phase III trials assessed a new combination of lenalidomide, bortezomib, and dexamethasone (RVD) in induction therapy in transplantation-eligible multiple myeloma (MM) patients, before consolidation with RVD and lenalidomide maintenance. We present a retrospective study evaluating this approach with patients from the real life. METHODS: We conducted a retrospective single-arm study to assess efficacy and safety of RVD combination in induction therapy before high-dose chemotherapy with melphalan followed by autologous stem cell transplantation, and RVD consolidation followed by lenalidomide maintenance, from February 2011 to May 2016. RESULTS: Forty patients were enrolled. The mean age at diagnosis was 56 years. Median progression-free survival was 45 months, and median overall survival was 76 months. The only factor found associated with better PFS was a negative minimal residual disease (P < .01). Twenty-six (65%) patients experimented adverse events: 8 patients (20%) underwent 12 serious AE (≥grade 3). Treatment discontinuation occurred in 2 patients (5%) because of severe AE. CONCLUSION: To our knowledge, this work provides the first evidence of the efficacy and the safety of RVD combination in patients treated in common practice.

[Geriatric failure to thrive: between illusory diagnosis and clinical reality]. / Syndrome de glissement : entre diagnostic illusoire et réalité clinique.

The geriatric failure to thrive, a controversial French concept not present in the international literature, was first characterized by Jean Carrié in 1956. It is described as a process of aging and physical and psychological decline associated with advanced age, manifesting as a pronounced overall deterioration. In this case report, we present the case of an 88-year-old patient, admitted to a general medicine service for geriatric failure to thrive, whose management eventually leads to the diagnosis of endocarditis with digestive cancer complicated by a characterized depressive episode. This case prompts us to consider the geriatric failure to thrive with extreme caution and challenges the legitimacy of such a diagnosis in the context of an aging population and the progress of medical sciences.

Polymyalgia rheumatica and giant cell arteritis following COVID-19 vaccination: Results from a nationwide survey.

We conducted a national in-depth analysis including pharmacovigilance reports and clinical study to assess the reporting rate (RR) and to determine the clinical profile of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) in COVID-19-vaccinated individuals. First, based on the French pharmacovigilance database, we estimated the RR of PMR and GCA cases in individuals aged over 50 who developed their initial symptoms within one month of receiving the BNT162b2 mRNA, mRNA-1273, ChAdOx1 nCoV-19, and Ad26.COV2.S vaccines. We then conducted a nationwide survey to gather clinical profiles, therapeutic management, and follow-up data from individuals registered in the pharmacovigilance study. A total of 70 854 684 COVID-19 vaccine doses were administered to 25 260 485 adults, among which, 179 cases of PMR (RR 7. 1 cases/1 000 000 persons) and 54 cases of GCA (RR 2. 1 cases/1 000 000 persons) have been reported. The nationwide survey allowed the characterization of 60 PMR and 35 GCA cases. Median time to the onset of first symptoms was 10 (range 2-30) and 7 (range 2-25) days for PMR and GCA, respectively. Phenotype, GCA-related ischemic complications and -large vessel vasculitis as well as therapeutic management and follow-up seemed similar according to the number of vaccine shots received and when compared to the literature data of unvaccinated population. Although rare, the short time between immunization and the onset of first symptoms of PMR and GCA suggests a temporal association. Physician should be aware of this potential vaccine-related phenomenon.

Categorization of patients with systemic lupus erythematosus using disease activity, patient-reported outcomes, and transcriptomic signatures.

OBJECTIVE: Patients with systemic lupus erythematosus (SLE) display symptoms that are not always related to disease activity and may distort clinical trial results. Recently, a clinical categorization based on the presence of type 1 (inflammatory manifestations) and/or type 2 (widespread pain, fatigue, depression) symptoms has been proposed in SLE. Our aim was to develop a type 2 score derived from the Short-Form health survey (SF-36) to categorize SLE patients and to compare immunological and transcriptomic profiles between groups. METHOD: Seventeen items from the SF-36 were selected to build a type 2 score for 50 SLE patients (100 visits; LUPUCE cohort), and the SLEDAI was used to define type 1 symptoms. Patients were categorized into four groups: minimal (no symptoms), type 1, type 2, and mixed (both type 1 and type 2 symptoms). Clinical, immunological, and transcriptomic profiles were compared between the groups. RESULTS: Type 2 scores ranged from 0 to 31, with a cutoff value of 14 (75th percentile). The sample categorization was minimal in 39%, type 1 in 37%, and type 2 in 9%, and mixed in 15%. Type 2 patients were older than minimal patients and had a longer disease duration than type 1 and mixed patients. Immunological data and modular interferon signatures did not differ between the groups. CONCLUSION: Patients with SLE can be categorized into four clinical groups using the SLEDAI score and our SF-36-derived type 2 score. This categorization is non-redundant with immunological or transcriptomic profiles and could prove useful to stratify patients in clinical trials. Key Points • A score derived from selected items of the SF-36 can be used to identify SLE patients with type 2 symptoms according to the Duke University categorization. • Using the SLEDAI and this type 2 score, SLE patients can be categorized into four clinical groups. • This categorization is not related to immunological activity or blood transcriptome profiles (and not to the interferon signature in particular). • This categorization could be useful in the daily care of patients as well as in clinical trials, for upstream patient stratification or for the interpretation of results.

Cytological Diagnosis of Classic Myeloproliferative Neoplasms at the Age of Molecular Biology.

Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell-derived disorders characterized by uncontrolled proliferation of differentiated myeloid cells. Two main groups of MPN, BCR::ABL1-positive (Chronic Myeloid Leukemia) and BCR::ABL1-negative (Polycythemia Vera, Essential Thrombocytosis, Primary Myelofibrosis) are distinguished. For many years, cytomorphologic and histologic features were the only proof of MPN and attempted to distinguish the different entities of the subgroup BCR::ABL1-negative MPN. World Health Organization (WHO) classification of myeloid neoplasms evolves over the years and increasingly considers molecular abnormalities to prove the clonal hematopoiesis. In addition to morphological clues, the detection of JAK2, MPL and CALR mutations are considered driver events belonging to the major diagnostic criteria of BCR::ABL1-negative MPN. This highlights the preponderant place of molecular features in the MPN diagnosis. Moreover, the advent of next-generation sequencing (NGS) allowed the identification of additional somatic mutations involved in clonal hematopoiesis and playing a role in the prognosis of MPN. Nowadays, careful cytomorphology and molecular biology are inseparable and complementary to provide a specific diagnosis and to permit the best follow-up of these diseases.

Anti-Jo-1 autoantibodies: biomarkers of severity and evolution of the disease in antisynthetase syndrome.

BACKGROUND: Anti-Jo-1 autoantibodies represent essential markers in the diagnosis of antisynthetase syndrome (ASS). In this retrospective study, we aimed to investigate whether their concentrations and fluctuations could both respectively reflect the severity and evolution of ASS. METHODS: Between 2015 and 2020, clinical and biological features of ASS patients with at least one positive measure of anti-Jo-1 autoantibody were collected. At each serum sampling, we assessed myositis activity by using the Myositis Intention to Treat Activities Index (MITAX) and compared anti-Jo-1 concentrations with ASS severity, anti-Jo-1 concentrations between patients with and without active disease, and changes in anti-Jo-1 concentrations with disease activity. RESULTS: Forty-eight patients with ASS had at least one positive determination of anti-Jo-1 concentration. Among them, twenty-nine patients had at least two determinations of anti-Jo-1 autoantibody in their follow-up. We showed that these autoantibody concentrations were significantly correlated with MITAX (r = 0.4, p = 0.03) and creatine kinase concentration (r = 0.34, p = 0.002) and that they were significantly higher in patients with active disease than in those with inactive disease (91.7 IU/L vs 44.4 IU/L, p = 0.016). During follow-up, we found a significant correlation between fluctuations of anti-Jo-1 autoantibody concentrations and MITAX score (r = 0.7, p < 0.0001). CONCLUSION: Our results suggest that anti-Jo-1 autoantibody concentration could be a predictive marker of the severity and evolution of ASS and show that their quantification could represent a precious tool for disease monitoring and for improving the therapeutic management of ASS patients.

Adipose Tissue and Adipose-Tissue-Derived Cell Therapies for the Treatment of the Face and Hands of Patients Suffering from Systemic Sclerosis.

Adipose tissue is recognized as a valuable source of cells with angiogenic, immunomodulatory, reparative and antifibrotic properties and emerged as a therapeutic alternative for the regeneration and repair of damaged tissues. The use of adipose-tissue-based therapy is expanding in autoimmune diseases, particularly in Systemic Sclerosis (SSc), a disease in which hands and face are severely affected, leading to disability and a decrease in quality of life. Combining the advantage of an abundant supply of fat tissue and a high abundance of stem/stromal cells, fat grafting and adipose tissue-derived cell-based therapies are attractive therapeutic options in SSc. This review aims to synthesize the evidence to determine the effects of the use of these biological products for face and hands treatment in the context of SSc. This highlights several points: the need to use relevant effectiveness criteria taking into account the clinical heterogeneity of SSc in order to facilitate assessment and comparison of innovative therapies; second, it reveals some impacts of the disease on fat-grafting success; third, an important heterogeneity was noticed regarding the manufacturing of the adipose-derived products and lastly, it shows a lack of robust evidence from controlled trials comparing adipose-derived products with standard care.

Tocilizumab versus anakinra in COVID-19: results from propensity score matching.

Background: Tocilizumab and anakinra are anti-interleukin drugs to treat severe coronavirus disease 2019 (COVID-19) refractory to corticosteroids. However, no studies compared the efficacy of tocilizumab versus anakinra to guide the choice of the therapy in clinical practice. We aimed to compare the outcomes of COVID-19 patients treated with tocilizumab or anakinra. Methods: Our retrospective study was conducted in three French university hospitals between February 2021 and February 2022 and included all the consecutive hospitalized patients with a laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection assessed by RT-PCR who were treated with tocilizumab or anakinra. A propensity score matching was performed to minimize confounding effects due to the non-random allocation. Results: Among 235 patients (mean age, 72 years; 60.9% of male patients), the 28-day mortality (29.4% vs. 31.2%, p = 0.76), the in-hospital mortality (31.7% vs. 33.0%, p = 0.83), the high-flow oxygen requirement (17.5% vs. 18.3%, p = 0.86), the intensive care unit admission rate (30.8% vs. 22.2%, p = 0.30), and the mechanical ventilation rate (15.4% vs. 11.1%, p = 0.50) were similar in patients receiving tocilizumab and those receiving anakinra. After propensity score matching, the 28-day mortality (29.1% vs. 30.4%, p = 1) and the rate of high-flow oxygen requirement (10.1% vs. 21.5%, p = 0.081) did not differ between patients receiving tocilizumab or anakinra. Secondary infection rates were similar between the tocilizumab and anakinra groups (6.3% vs. 9.2%, p = 0.44). Conclusion: Our study showed comparable efficacy and safety profiles of tocilizumab and anakinra to treat severe COVID-19.

Combining systemic and locally applied cellular therapies for the treatment of systemic sclerosis.

Systemic sclerosis (SSc) is a complex autoimmune disease characterized by a functional and structural alteration of the microvascular network associated with cutaneous and visceral fibrosis lesions. Conventional therapies are based on the use of immunomodulatory molecules and symptomatic management but often prove to be insufficient, particularly for patients suffering from severe and rapidly progressive forms of the disease. In this context, cellular therapy approaches could represent a credible solution with the goal to act on the different components of the disease: the immune system, the vascular system and the extracellular matrix. The purpose of this review is to provide an overview of the cellular therapies available for the management of SSc. The first part will focus on systemically injected therapies, whose primary effect is based on immunomodulatory properties and immune system resetting, including autologous hematopoietic stem cell transplantation and intravenous injection of mesenchymal stem cells. The second part will discuss locally administered regenerative cell therapies, mainly derived from adipose tissue, developed for the management of local complications as hand and face disabilities.

Anti-cardiolipin IgG autoantibodies associate with circulating extracellular DNA in severe COVID-19.

Whereas the detection of antiphospholipid autoantibodies (aPL) in COVID-19 is of increasing interest, their role is still unclear. We analyzed a large aPL panel in 157 patients with COVID-19 according to the disease severity. We also investigated a potential association between aPL and extracellular DNA (exDNA, n = 85) or circulating markers of neutrophil extracellular traps (NET) such as citrullinated histones H3 (CitH3, n = 49). A total of 157 sera of patients infected by SARS-CoV-2 were collected. A large aPL panel including lupus anticoagulant, anti-cardiolipin and anti-beta-2 glycoprotein I (IgG, IgM and IgA), anti-phosphatidylethanolamine IgA, anti-prothrombin (IgG and IgM) was retrospectively analyzed according to the disease severity. We found a total aPL prevalence of 54.8% with almost half of the cases having aCL IgG. Within an extended panel of aPL, only aCL IgG were associated with COVID-19 severity. Additionally, severe patients displayed higher CitH3 levels than mild patients. Interestingly, we highlighted a significant association between the levels of aCL IgG and exDNA only in aCL positive patients with severe disease. In conclusion, we showed a significant link between aPL, namely aCL IgG, and circulating exDNA in patients with severe form of COVID-19, that could exacerbate the thrombo-inflammatory state related to disease severity.

Functional status in older patients with cancer.

BACKGROUND: Functional Status (FS) is an important domain in Comprehensive Geriatric Assessment (CGA) and is most often evaluated using the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales separately. METHOD AND OBJECTIVES: This secondary analysis of a previous prospective cohort study was conducted between September 2015 and May 2018 at Marseille University Hospital, France, on 613 cancer outpatients aged ≥70 years. The first objective of this study was to determine the prevalence of FS impairment in older outpatients with cancer using a combination of the information collected with the ADL and short IADL scales. Our second objective was to describe the potential impact of this combined FS on three-month unplanned hospitalizations and three-month mortality in this population. RESULTS: The median age was 81 years and 61.2% were men. The most common types of tumours were lung and thoracic (22.3%). Concerning FS, 255 patients (41.6%) had unimpaired ADL-IADL, 131 patients (21.4%) had IADL impairment, 38 patients (6.2%) had ADL impairment, and 189 patients (30.8%) had impaired ADL-IADL. In the multivariate Cox analysis, metastatic stage (adjusted Hazard Ratio (aHR) = 1.79; 95% CI [1.14-2.80]) and impaired ADL-IADL (aHR = 3.46; 95% CI [1.89-6.33]) were independently associated with three-month mortality. In the logistic regression model, impaired ADL-IADL (adjusted Odd ratio (aOR) = 3.64; 95% CI [1.84-7.20]) was the only factor independently associated with three-month unplanned hospitalizations. INTERPRETATION: The combined use of the ADL and IADL scales to evaluate functional status in older patients with cancer is of significant prognostic value regarding the risks of three-month unplanned hospitalizations and mortality.

Impact of Molecular Biology in Diagnosis, Prognosis, and Therapeutic Management of BCR::ABL1-Negative Myeloproliferative Neoplasm.

BCR::ABL1-negative myeloproliferative neoplasms (MPNs) include three major subgroups-polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF)-which are characterized by aberrant hematopoietic proliferation with an increased risk of leukemic transformation. Besides the driver mutations, which are JAK2, CALR, and MPL, more than twenty additional mutations have been identified through the use of next-generation sequencing (NGS), which can be involved with pathways that regulate epigenetic modifications, RNA splicing, or DNA repair. The aim of this short review is to highlight the impact of molecular biology on the diagnosis, prognosis, and therapeutic management of patients with PV, ET, and PMF.