Abstract
Objective
We examined whether diabetic ketoacidosis (DKA), a serious complication of type 1 diabetes (T1D) was more prevalent among Non-Hispanic (NH) Black and Hispanic patients with T1D and ...laboratory-confirmed coronavirus disease 2019 (COVID-19) compared with NH Whites.
Method
This is a cross-sectional study of patients with T1D and laboratory-confirmed COVID-19 from 52 clinical sites in the United States, data were collected from April to August 2020. We examined the distribution of patient factors and DKA events across NH White, NH Black, and Hispanic race/ethnicity groups. Multivariable logistic regression analysis was performed to examine the odds of DKA among NH Black and Hispanic patients with T1D as compared with NH White patients, adjusting for potential confounders, such as age, sex, insurance, and last glycated hemoglobin A1c (HbA1c) level.
Results
We included 180 patients with T1D and laboratory-confirmed COVID-19 in the analysis. Forty-four percent (n = 79) were NH White, 31% (n = 55) NH Black, 26% (n = 46) Hispanic. NH Blacks and Hispanics had higher median HbA1c than Whites (%-points IQR: 11.7 4.7, P < 0.001, and 9.7 3.1 vs 8.3 2.4, P = 0.01, respectively). We found that more NH Black and Hispanic presented with DKA compared to Whites (55% and 33% vs 13%, P < 0.001 and P = 0.008, respectively). After adjusting for potential confounders, NH Black patients continued to have greater odds of presenting with DKA compared with NH Whites (OR 95% CI: 3.7 1.4, 10.6).
Conclusion
We found that among T1D patients with COVID-19 infection, NH Black patients were more likely to present in DKA compared with NH White patients. Our findings demonstrate additional risk among NH Black patients with T1D and COVID-19.
There is no detailed comparison of allergen-specific immunoglobulin responses following sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT).
We sought to compare nasal and systemic ...timothy grass pollen (TGP)-specific antibody responses during 2 years of SCIT and SLIT and 1 year after treatment discontinuation in a double-blind, double-dummy, placebo-controlled trial.
Nasal fluid and serum were obtained yearly (per-protocol population, n = 84). TGP-specific IgA1, IgA2, IgG4, IgG, and IgE were measured in nasal fluids by ELISA. TGP-specific IgA1, IgA2, and Phleum pratense (Phl p)1, 2, 4, 5b, 6, 7, 11, and 12 IgE and IgG4 were measured in sera by ELISA and ImmunoCAP, respectively.
At years 2 and 3, TGP-IgA1/2 levels in nasal fluid were elevated in SLIT compared with SCIT (4.2- and 3.0-fold for IgA1, 2.0- and 1.8-fold for IgA2, respectively; all P < .01). TGP-IgA1 level in serum was elevated in SLIT compared with SCIT at years 1, 2, and 3 (4.6-, 5.1-, and 4.7-fold, respectively; all P < .001). Serum TGP-IgG level was higher in SCIT compared with SLIT (2.8-fold) at year 2. Serum TGP-IgG4 level was higher in SCIT compared with SLIT at years 1, 2, and 3 (10.4-, 27.4-, and 5.1-fold, respectively; all P < .01). Serum IgG4 levels to Phl p1, 2, 5b, and 6 were increased at years 1, 2, and 3 in SCIT and SLIT compared with placebo (Phl p1: 11.8- and 3.9-fold; Phl p2: 31.6- and 4.4-fold; Phl p5b: 135.5- and 5.3-fold; Phl p6: 145.4- and 14.7-fold, respectively, all at year 2 when levels peaked; P < .05). IgE to TGP in nasal fluid increased in the SLIT group at year 2 but not at year 3 compared with SCIT (2.8-fold; P = .04) and placebo (3.1-fold; P = .02). IgA to TGP and IgE and IgG4 to TGP components stratified participants according to treatment group and clinical response.
The observed induction of IgA1/2 in SLIT and IgG4 in SCIT suggest key differences in the mechanisms of action.
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Summary Background Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune ...mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved β-cell function in recent-onset type 1 diabetes. Methods We did two randomised, placebo-controlled trials in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test-stimulated C peptide of at least 0·2 nM. Patients in the canakinumab trial were aged 6–45 years and those in the anakinra trial were aged 18–35 years. Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe. Participants were randomly assigned by computer-generated blocked randomisation to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. Participants and carers were masked to treatment assignment. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial). Analyses were by intention to treat. These studies are registered with ClinicalTrials.gov , numbers NCT00947427 and NCT00711503 , and EudraCT number 2007-007146-34. Findings Patients were enrolled in the canakinumab trial between Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 26, 2009, and May 25, 2011. 69 patients were randomly assigned to canakinumab (n=47) or placebo (n=22) monthly for 12 months and 69 were randomly assigned to anakinra (n=35) or placebo (n=34) daily for 9 months. No interim analyses were done. 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses. The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0·01 nmol/L (95% CI −0·11 to 0·14; p=0·86), and between the anakinra and the placebo groups at 9 months was 0·02 nmol/L (–0·09 to 0·15; p=0·71). The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p=0·018), which was mainly because of a higher number of injection site reactions in the anakinra group. Interpretation Canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1 diabetes. Interleukin-1 blockade might be more effective in combination with treatments that target adaptive immunity in organ-specific autoimmune disorders. Funding National Institutes of Health and Juvenile Diabetes Research Foundation.
The mechanisms that promote an inflammatory environment and accelerated atherosclerosis in diabetes are poorly understood. We show that macrophages isolated from two different mouse models of type 1 ...diabetes exhibit an inflammatory phenotype. This inflammatory phenotype associates with increased expression of long-chain acyl-CoA synthetase 1 (ACSL1), an enzyme that catalyzes the thioesterification of fatty acids. Monocytes from humans and mice with type 1 diabetes also exhibit increased ACSL1. Furthermore, myeloid-selective deletion of ACSL1 protects monocytes and macrophages from the inflammatory effects of diabetes. Strikingly, myeloid-selective deletion of ACSL1 also prevents accelerated atherosclerosis in diabetic mice without affecting lesions in nondiabetic mice. Our observations indicate that ACSL1 plays a critical role by promoting the inflammatory phenotype of macrophages associated with type 1 diabetes; they also raise the possibilities that diabetic atherosclerosis has an etiology that is, at least in part, distinct from the etiology of nondiabetic vascular disease and that this difference is because of increased monocyte and macrophage ACSL1 expression.
Islet autoantibodies are predominantly measured by radioassay to facilitate risk assessment and diagnosis of type 1 diabetes. However, the reliance on radioactive components, large sample volumes and ...limited throughput renders radioassay testing costly and challenging. We developed a multiplex analysis platform based on antibody detection by agglutination-PCR (ADAP) for the sample-sparing measurement of GAD, IA-2 and insulin autoantibodies/antibodies in 1 μL serum. The assay was developed and validated in 7 distinct cohorts (n = 858) with the majority of the cohorts blinded prior to analysis. Measurements from the ADAP assay were compared to radioassay to determine correlation, concordance, agreement, clinical sensitivity and specificity. The average overall agreement between ADAP and radioassay was above 91%. The average clinical sensitivity and specificity were 96% and 97%. In the IASP 2018 workshop, ADAP achieved the highest sensitivity of all assays tested at 95% specificity (AS95) rating for GAD and IA-2 autoantibodies and top-tier performance for insulin autoantibodies. Furthermore, ADAP correctly identified 95% high-risk individuals with two or more autoantibodies by radioassay amongst 39 relatives of T1D patients tested. In conclusion, the new ADAP assay can reliably detect the three cardinal islet autoantibodies/antibodies in 1μL serum with high sensitivity. This novel assay may improve pediatric testing compliance and facilitate easier community-wide screening for islet autoantibodies.
Background
Diabetes is a risk factor for poor COVID‐19 outcomes, but pediatric patients with type 1 diabetes are poorly represented in current studies.
Methods
T1D Exchange coordinated a US type 1 ...diabetes COVID‐19 registry. Forty‐six diabetes centers submitted pediatric cases for patients with laboratory confirmed COVID‐19. Associations between clinical factors and hospitalization were tested with Fisher's Exact Test. Logistic regression was used to calculate odds ratios for hospitalization.
Results
Data from 266 patients with previously established type 1 diabetes aged <19 years with COVID‐19 were reported. Diabetic ketoacidosis (DKA) was the most common adverse outcome (n = 44, 72% of hospitalized patients). There were four hospitalizations for severe hypoglycemia, three hospitalizations requiring respiratory support (one of whom was intubated and mechanically ventilated), one case of multisystem inflammatory syndrome in children, and 10 patients who were hospitalized for reasons unrelated to COVID‐19 or diabetes. Hospitalized patients (n = 61) were more likely than nonhospitalized patients (n = 205) to have minority race/ethnicity (67% vs 39%, P < 0.001), public insurance (64% vs 41%, P < 0.001), higher A1c (11% 97 mmol/mol vs 8.2% 66 mmol/mol, P < 0.001), and lower insulin pump and lower continuous glucose monitoring use (26% vs 54%, P < 0.001; 39% vs 75%, P < 0.001). Age and gender were not associated with risk of hospitalization. Higher A1c was significantly associated with hospitalization, with an odds ratio of 1.56 (1.34‐1.84) after adjusting for age, gender, insurance, and race/ethnicity.
Conclusions
Higher A1c remained the only predictor for hospitalization with COVID‐19. Diabetic ketoacidosis is the primary concern among this group.
摘要
背景
糖尿病是新型冠状病毒肺炎预后差的危险因素, 但在目前的研究中, 1型糖尿病儿童患者的情况鲜有报道。
方法T1D交流处协调了一个美国新型冠状病毒肺炎1型糖尿病的临床注册研究。46个糖尿病中心提交了实验室确认的新型冠状病毒肺炎患者的儿童病例。采用Fisher‘s 确切检验分析临床因素与住院时间的相关性。用Logistic回归计算住院的优势比。
结果报道了266例既往确诊的<19岁的1型糖尿病患者患有新型冠状病毒肺炎的资料。糖尿病酮症酸中毒(DKA)是最常见的不良结局(n=44, 72%的住院患者)。因严重低血糖住院4例, 需要呼吸支持住院3例(其中1例经气管插管机械通气), 1例儿童多系统炎症综合征, 10例因与新型冠状病毒肺炎或糖尿病无关的原因住院。住院患者(n=61)与非住院患者(n=205)相比:少数族裔占比更高(67%比39%, P<0.001)、公共保险覆盖率更高(64%比41%, P<0.001)、糖化血红蛋白更高(11%97 mmol/mol比8.2%66 mmol/mol, P<0.001)、胰岛素泵以及连续血糖监测系统使用率更低(26%比54%, P<0.001, 39%比75%, P<0.001)。年龄和性别与住院风险无关。较高的糖化血红蛋白与住院显著相关, 在校正了年龄、性别、保险和种族后, 优势比为1.56(1.34‐1.84)。
结论较高的糖化血红蛋白仍然是新型冠状病毒肺炎住院的唯一预测因素。糖尿病酮症酸中毒是这一群体的首要问题。
Highlights Outcomes for children with type 1 diabetes who experience COVID‐19 are currently unknown. We report 266 cases from US diabetes clinics of children with type 1 diabetes who had COVID‐19. Diabetic ketoacidosis was the major adverse outcome, and it was associated with higher A1c.
The development of rational approaches to restore immune tolerance requires an iterative approach that builds on past success and utilizes new mechanistic insights into immune-mediated pathologies. ...This article will review concepts that have evolved from the clinical trial experience of the Immune Tolerance Network, with an emphasis on lessons learned from the innovative mechanistic studies conducted for these trials and new strategies under development for induction of tolerance.
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