Increased risk of severe COVID-19 in hospitalized patients with SARS-CoV-2 Alpha variant infection: a multicentre matched cohort study.

BACKGROUND: The impact of the variant of concern (VOC) Alpha on the severity of COVID-19 has been debated. We report our analysis in France. METHODS: We conducted an exposed/unexposed cohort study with retrospective data collection, comparing patients infected by VOC Alpha to contemporaneous patients infected by historical lineages. Participants were matched on age (± 2.5 years), sex and region of hospitalization. The primary endpoint was the proportion of hospitalized participants with severe COVID-19, defined as a WHO-scale > 5 or by the need of a non-rebreather mask, occurring up to day 29 after admission. We used a logistic regression model stratified on each matched pair and accounting for factors known to be associated with the severity of the disease. RESULTS: We included 650 pairs of patients hospitalized between Jan 1, 2021, and Feb 28, 2021, in 47 hospitals. Median age was 70 years and 61.3% of participants were male. The proportion of participants with comorbidities was high in both groups (85.0% vs 90%, p = 0.004). Infection by VOC Alpha was associated with a higher odds of severe COVID-19 (41.7% vs 38.5%-aOR = 1.33 95% CI [1.03-1.72]). CONCLUSION: Infection by the VOC Alpha was associated with a higher odds of severe COVID-19.

What is the impact of blood pressure on neurological symptoms and the risk of ESKD in primary and secondary thrombotic microangiopathies based on clinical presentation: a retrospective study.

BACKGROUND: The impact of blood pressure on neurological symptoms and risk of end-stage kidney disease (ESKD) is unknown in primary and secondary thrombotic microangiopathies (TMAs). METHODS: We measured baseline systolic (SBP) and diastolic (DBP) BP in consecutive 563 patients with adjudicated primary and secondary TMAs, and assessed its association with the risk of ESKD. RESULTS: Normal BP, grade 1, 2 and 3 hypertension were present in 243 (43.1%), 132 (23.4%), 101 (17.9%) and 88 (15.6%), respectively. Significant BP differences were noted in relation to the cause of TMA: highest BP values were found in patients with atypical hemolytic-uremic syndrome (aHUS), pregnancy, transplantation and auto-immune-related TMAs. Normal BP or grade 1 hypertension was found in 17/18 (94.4%) patients with thrombotic thrombocytopenic patients (only 1/18 (5.6%) had a SBP value>150 mmHg). In contrast, BP values could not differentiate isolated "essential" malignant hypertension (MH) from MH associated with aHUS (isolated MH (n=15): BP (median (IQR)): 220 (182-249)/132 (101-150) mmHg; MH with aHUS (n=5): BP: 223 (196-245)/131 (111-144) mmHg). The risk of vigilance disturbances (6.9%, 15.0%, 25.0%, respectively), epileptic seizures (1.5%, 4.0%, 12.5%, respectively) and posterior reversible encephalopathy syndrome (0.76%, 2.97%, 6.82%, respectively) increased with increasing baseline BP values from grade 1 to grade 3 hypertension. ESKD occurred in 35/563 (6.2%) patients (1.23%, 2.27%, 11.9% and 19.3% of patients with normal BP, grade 1, 2 and 3 hypertension, respectively). As compared to patients with normal BP (<120/139 mmHg), grade 1, grade 2 and grade 3 hypertension were associated with a greater risk of ESKD in univariate (OR: 1.91 [0.83-4.40], 13.2 [3.56-48.9] and 34.8 [9.31-130], respectively) and multivariate (OR: 0.89 [0.30-2.69], 7.00 [1.57-31.3] and 19.7 [4.53-85.2], respectively) analyses. The association between BP and the risk of ESRD was unchanged after adjustment on eculizumab use (OR: 3.46 [1.41-8.49], 17.7 [4.44-70.0] and 70.6 [8.61-579], respectively). Patients with MH, regardless of its cause, had a greater risk of ESKD (OR: 26.4 [10.0-69.8] vs other patients). CONCLUSIONS: Baseline BP differs in primary and secondary TMAs. High BP reduces the neurological tolerance of TMAs and is a powerful independent risk factor of ESKD, even after adjustment on TMA's cause.

The French Society of Internal Medicine's Top-5 List of Recommendations: a National Web-Based Survey.

BACKGROUND: The international project "Choosing Wisely" aims to target unnecessary and potentially harmful examinations and treatments. OBJECTIVE: To define the French Internal Medicine Top-5 list. DESIGN: Based on a review of existing Top-5 lists and personal experience, a working group of the French National Society of Internal Medicine selected 27 diagnostic and therapeutic procedures. They were submitted through a national web-based survey to French internists who rated from 1 to 5 the perceived frequency, uselessness, and risk of each procedure. A composite score was calculated as the unweighted addition of the three scores. PARTICIPANTS: Four hundred thirty internists answered the web-based survey (14% of all French internists including residents). All the French regions and status of the profession were represented. KEY RESULTS: For the 27 submitted procedures, the mean score (± SD) was 3.25 (± 0.48) for frequency, 3.10 (± 0.43) for uselessness, and 2.63 (± 0.84) for risk. The Top-5 list obtained with the composite score was as follows: 1. Do not prescribe long-term treatment with proton pump inhibitors without regular reevaluation of the indication 2. Do not administer preventive treatments (e.g., for dyslipidemia, hypertension…) in elderly people with dementia when potential risks outweigh the benefits 3. Do not administer hypnotic medications as first-line treatment for insomnia 4. Do not treat with an anticoagulant for more than 3 months a patient with a first venous thromboembolism occurring in the setting of a major transient risk factor 5. Do not screen for Lyme disease without an exposure history or related clinical examination findings We found that the composite score was strongly correlated to the risk score (rs = 0.88, p < 10-5) and not to the frequency (rs = 0.06, p = 0.75) or uselessness score (rs = 0.17, p = 0.38). CONCLUSIONS: This Top-5 list provides an opportunity to discuss appropriate use of health care practices in internal medicine.

Systemic Histiocytosis (Langerhans Cell Histiocytosis, Erdheim-Chester Disease, Destombes-Rosai-Dorfman Disease): from Oncogenic Mutations to Inflammatory Disorders.

PURPOSE OF REVIEW: Provide an overview of recent progress in decoding the pathogenesis and treatment of systemic histiocytoses. RECENT FINDINGS: Advances in molecular techniques over the last few years, enabling the identification of several MAPK mutations in lesion histiocytes, have revolutionized our understanding of histiocytosis that led to a revised classification and new treatments. Since the 2010 discovery of the BRAFV600E mutation in 57% of Langerhans cell histiocytosis (LCH) lesions, several other kinase mutations have been found, mostly in the MAPK pathway, and also in other key signaling pathways, in LCH, Erdheim-Chester Disease (ECD) and, less frequently, Destombes-Rosai-Dorfman disease (RDD). Those revolutionary breakthroughs enhanced our understanding of the pathogenesis of histiocytosis and led to trials with targeted therapies that demonstrated notable efficacy.

Infection in Patients with Suspected Thrombotic Microangiopathy Based on Clinical Presentation.

BACKGROUND AND OBJECTIVES: In contrast to shigatoxin-associated Escherichia coli (STEC) causing hemolytic uremic syndrome, STEC-unrelated infections associated with thrombotic microangiopathy are less characterized. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our retrospective study in a four-hospital institution of 530 consecutive patients with adjudicated thrombotic microangiopathies during the 2009-2016 period studied STEC-unrelated infections' epidemiology and major outcomes (death, acute dialysis, and major cardiovascular events). RESULTS: STEC-unrelated infection was present in 145 of 530 (27%) patients, thrombotic microangiopathies without infection were present in 350 of 530 (66%) patients, and STEC causing hemolytic and uremic syndrome was present in 35 of 530 (7%) patients. They (versus thrombotic microangiopathy without infection) were associated with age >60 years (36% versus 18%), men (53% versus 27%), altered consciousness (32% versus 11%), mean BP <65 mm Hg (21% versus 4%), lower hemoglobin and platelet count, and AKI (72% versus 49%). They were associated with more than one pathogen in 36 of 145 (25%) patients (either isolated [14%] or combined [86%] to other causes of thrombotic microangiopathy); however, no significant clinical or biologic differences were noted between the two groups. They were more frequently due to bacteria (enterobacteria [41%], Staphylococcus aureus [11%], and Streptococcus pneumonia [3%]) than viruses (Epstein-Barr [20%], cytomegalovirus [18%], influenza [3%], hepatitis C [1%], HIV [1%], and rotavirus [1%]). STEC-unrelated infections were independent risk factors for in-hospital death (odds ratio, 2.22; 95% confidence interval, 1.18 to 4.29), major cardiovascular event (odds ratio, 3.43; 95% confidence interval, 1.82 to 6.69), and acute dialysis (odds ratio, 3.48; 95% confidence interval, 1.78 to 7.03). Bacteria (versus other pathogens), and among bacteria, enterobacteria, presence of more than one bacteria, and E. coli without shigatoxin were risk factors for acute dialysis. CONCLUSIONS: Infections are frequent thrombotic microangiopathy triggers or causes, and they are mostly unrelated to STEC. Infections convey a higher risk of death and major complications. The most frequent pathogens were enterobacteria, S. aureus, Epstein-Barr virus, and cytomegalovirus. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_09_07_CJN17511120.mp3.

Tissue Infiltrating LTi-Like Group 3 Innate Lymphoid Cells and T Follicular Helper Cells in Graves' and Hashimoto's Thyroiditis.

Background: Hashimoto's thyroiditis (HT) and Graves' disease (GD) are autoimmune thyroid disorders (AITDs). These conditions have been associated to abnormalities in circulating regulatory T cells (Tregs). We postulated that immune perturbations could be more pronounced at the thyroid tissue level. Methods: The phenotype of PBMCs and immune cells infiltrating thyroid tissue from 19 patients with HT, 21 patients with GD, and 30 controls has been analyzed by flow cytometry. Results: We report that blood and thyroid Treg cell subsets are similarly represented in all AITDs patients and controls. Increased Lymphoid tissue inducer (LTi)-like ILC3 and CXCR5+ PD-1hi CD4+ T follicular helper cells (Tfh) tissue-infiltrating cells, together with the prevalence of tertiary lymphoid structures (TLS) and germinal centers (GCs) represented a typical immune signature in all HT and 60% of GD patients. In the remaining group of GD patients, the absence of the aforementioned abnormalities was associated with a higher prevalence of ophthalmopathy. Conclusion: Tissue infiltrating Lymphoid Tissue inducer-like group 3 Innate Lymphoid cells and T follicular helper cells are increased in most thyroid autoimmune disease.

[Monoclonal antibodies for monogenic diseases: a 2019 update]. / Actualités des anticorps monoclonaux dans les maladies monogéniques aujourd'hui.

Monogenic diseases are rare genetic diseases but they are numerous and display a highly variable degree of severity. First uses of monoclonal antibodies to treat monogenic diseases started in the 2000's and many clinical trials are ongoing. Anti-IL-1ß therapies have greatly modified the outcome of auto-inflammatory diseases by modulating inflammatory response and reducing the risk of secondary amyloidosis. Anti-TNF-α are also used in such diseases. In atypical hemolytic and uremic syndrome due to deficiencies in the control of alternative complement pathway, eculizumab, an anti-C5 monoclonal antibody, has improved renal outcome in treated patients. More recently, lanadelumab, an anti-plasma kallikrein antibody, has reinforced the therapeutic arsenal in hereditary angioedema and burosumab, anti-FGF23, that of X-linked hypophosphatemia. Such examples reflect the importance of monoclonal antibody therapy of monogenic diseases, the interest of considering such an option as well as the need for future researches.

TITLE: Actualités des anticorps monoclonaux dans les maladies monogéniques aujourd'hui. ABSTRACT: Les maladies monogéniques sont des maladies génétiques rares mais très nombreuses, avec une sévérité variable. Les premières utilisations des anticorps monoclonaux dans ces maladies remontent aux années 2000 et de nombreux essais sont désormais en cours. Les anticorps monoclonaux anti-(interleukine)IL-1ß ont profondément transformé la prise en charge des maladies auto-inflammatoires en modulant la composante inflammatoire et en diminuant le risque d'amylose secondaire ; les anticorps monoclonaux anti-TNF-α et anti-IL-6 sont également prescrits dans ces maladies. Dans le syndrome hémolytique et urémique atypique lié à des défauts de régulation de la voie alterne du complément, l'éculizumab, un anticorps monoclonal anti-C5, a permis d'améliorer le pronostic rénal des patients traités. Plus récemment, le lanadélumab, un anticorps monoclonal anti-kallicréïne plasmatique, est venu renforcer l'arsenal thérapeutique des angiœdèmes héréditaires et le burosumab, un anticorps monoclonal anti-FGF23, celui du rachitisme hypophosphatémique lié à l'X. Ces exemples illustrent bien l'importance de l'utilisation des anticorps monoclonaux dans la prise en charge des maladies monogéniques, l'intérêt de considérer cette option thérapeutique dans ce domaine et la nécessité de poursuivre des recherches.

Etiology and Outcomes of Thrombotic Microangiopathies.

BACKGROUND AND OBJECTIVES: Thrombotic microangiopathies constitute a diagnostic and therapeutic challenge. Secondary thrombotic microangiopathies are less characterized than primary thrombotic microangiopathies (thrombotic thrombocytopenic purpura and atypical hemolytic and uremic syndrome). The relative frequencies and outcomes of secondary and primary thrombotic microangiopathies are unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a retrospective study in a four-hospital institution in 564 consecutive patients with adjudicated thrombotic microangiopathies during the 2009-2016 period. We estimated the incidence of primary and secondary thrombotic microangiopathies, thrombotic microangiopathy causes, and major outcomes during hospitalization (death, dialysis, major cardiovascular events [acute coronary syndrome and/or acute heart failure], and neurologic complications [stroke, cognitive impairment, or epilepsy]). RESULTS: We identified primary thrombotic microangiopathies in 33 of 564 patients (6%; thrombotic thrombocytopenic purpura: 18 of 564 [3%]; atypical hemolytic and uremic syndrome: 18 of 564 [3%]). Secondary thrombotic microangiopathies were found in 531 of 564 patients (94%). A cause was identified in 500 of 564 (94%): pregnancy (35%; 11 of 1000 pregnancies), malignancies (19%), infections (33%), drugs (26%), transplantations (17%), autoimmune diseases (9%), shiga toxin due to Escherichia coli (6%), and malignant hypertension (4%). In the 31 of 531 patients (6%) with other secondary thrombotic microangiopathies, 23% of patients had sickle cell disease, 10% had glucose-6-phosphate dehydrogenase deficiency, and 44% had folate deficiency. Multiple causes of thrombotic microangiopathies were more frequent in secondary than primary thrombotic microangiopathies (57% versus 19%; P<0.001), and they were mostly infections, drugs, transplantation, and malignancies. Significant differences in clinical and biologic differences were observed among thrombotic microangiopathy causes. During the hospitalization, 84 of 564 patients (15%) were treated with dialysis, 64 of 564 patients (11%) experienced major cardiovascular events, and 25 of 564 patients (4%) had neurologic complications; 58 of 564 patients (10%) died, but the rates of complications and death varied widely by the cause of thrombotic microangiopathies. CONCLUSIONS: Secondary thrombotic microangiopathies represent the majority of thrombotic microangiopathies. Multiple thrombotic microangiopathies causes are present in one half of secondary thrombotic microangiopathies. The risks of dialysis, neurologic and cardiac complications, and death vary by the cause of thrombotic microangiopathies.