| 1. |
- Bastard, P, et al.
(författare)
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Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs
- 2022
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Ingår i: Science immunology. - : American Association for the Advancement of Science (AAAS). - 2470-9468. ; 78:7490, s. eabp8966-
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Tidskriftsartikel (refereegranskat)abstract
- Life-threatening ‘breakthrough’ cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS-CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals (age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, while two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.
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| 2. |
- Kwon, Bum Chul, et al.
(författare)
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Islet Autoantibody Levels Differentiate Progression Trajectories in Individuals with Presymptomatic Type 1 Diabetes
- 2022
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 71:12, s. 2632-2641
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Tidskriftsartikel (refereegranskat)abstract
- Our previous data-driven analysis of evolving patterns of islet autoantibodies (IAbs) against insulin (IAA), glutamic acid decarboxylase (GADA) and islet antigen 2 (IA-2A) discovered three trajectories characterized by either multiple IAbs (TR1), IAA (TR2), or GADA (TR3) as the first appearing autoantibodies. Here we examined the evolution of IAb levels within these trajectories in 2,145 IAb-positive participants followed from early life and compared those who progressed to type 1 diabetes (n=643) to those remaining undiagnosed (n=1,502). Using thresholds determined by 5-year diabetes risk, four levels were defined for each IAb and overlayed onto each visit. In diagnosed participants, high IAA levels were seen in TR1 and TR2 at ages <3 years, whereas IAA remained at lower levels in the undiagnosed. Proportions of dwell times (total duration of follow-up at a given level) at the four IAb levels differed between the diagnosed and undiagnosed for GADA and IA-2A in all three trajectories (p<0.001), but for IAA dwell times differed only within TR2 (p<0.05). Overall, undiagnosed participants more frequently had low IAb levels and later appearance of IAb than diagnosed participants. In conclusion, while it has been long appreciated that the number of autoantibodies is an important predictor of type 1 diabetes, consideration of autoantibody levels within the three autoimmune trajectories improved differentiation of IAb positive children who progressed to type 1 diabetes from those who did not.
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| 3. |
- Kwon, Bum Chul, et al.
(författare)
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Progression of type 1 diabetes from latency to symptomatic disease is predicted by distinct autoimmune trajectories
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Development of islet autoimmunity precedes the onset of type 1 diabetes in children, however, the presence of autoantibodies does not necessarily lead to manifest disease and the onset of clinical symptoms is hard to predict. Here we show, by longitudinal sampling of islet autoantibodies (IAb) to insulin, glutamic acid decarboxylase and islet antigen-2 that disease progression follows distinct trajectories. Of the combined Type 1 Data Intelligence cohort of 24662 participants, 2172 individuals fulfill the criteria of two or more follow-up visits and IAb positivity at least once, with 652 progressing to type 1 diabetes during the 15 years course of the study. Our Continuous-Time Hidden Markov Models, that are developed to discover and visualize latent states based on the collected data and clinical characteristics of the patients, show that the health state of participants progresses from 11 distinct latent states as per three trajectories (TR1, TR2 and TR3), with associated 5-year cumulative diabetes-free survival of 40% (95% confidence interval [CI], 35% to 47%), 62% (95% CI, 57% to 67%), and 88% (95% CI, 85% to 91%), respectively (p < 0.0001). Age, sex, and HLA-DR status further refine the progression rates within trajectories, enabling clinically useful prediction of disease onset.
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| 4. |
- Li, Zhiguo, et al.
(författare)
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Childhood Height Growth Rate Association With the Risk of Islet Autoimmunity and Development of Type 1 Diabetes
- 2022
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 107:6, s. 1520-1528
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Tidskriftsartikel (refereegranskat)abstract
- Context: Rapid growth has been suggested to promote islet autoimmunity and progression to type 1 diabetes (T1D). Childhood growth has not been analyzed separately from the infant growth period in most previous studies, but it may have distinct features due to differences between the stages of development. Objective: We aimed to analyze the association of childhood growth with development of islet autoimmunity and progression to T1D diagnosis in children 1 to 8 years of age. Methods: Longitudinal data of childhood growth and development of islet autoimmunity and T1D were analyzed in a prospective cohort study including 10 145 children from Finland, Germany, Sweden, and the United States, 1-8 years of age with at least 3 height and weight measurements and at least 1 measurement of islet autoantibodies. The primary outcome was the appearance of islet autoimmunity and progression from islet autoimmunity to T1D. Results: Rapid increase in height (cm/year) was associated with increased risk of seroconversion to glutamic acid decarboxylase autoantibody, insulin autoantibody, or insulinoma-like antigen-2 autoantibody (hazard ratio [HR] = 1.26 [95% CI = 1.05, 1.51] for 1-3 years of age and HR = 1.48 [95% CI = 1.28, 1.73] for >3 years of age). Furthermore, height rate was positively associated with development of T1D (HR = 1.80 [95% CI = 1.15, 2.81]) in the analyses from seroconversion with insulin autoantibody to diabetes. Conclusion: Rapid height growth rate in childhood is associated with increased risk of islet autoimmunity and progression to T1D. Further work is needed to investigate the biological mechanism that may explain this association.
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| 5. |
- Ng, Kenney, et al.
(författare)
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Islet Autoantibody Type-Specific Titer Thresholds Improve Stratification of Risk of Progression to Type 1 Diabetes in Children
- 2022
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992. ; 45:1, s. 160-168
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE To use islet autoantibody titers to improve the estimation of future type 1 diabetes risk in children. RESEARCH DESIGN AND METHODS Prospective cohort studies in Finland, Germany, Sweden, and the U.S. followed 24,662 children at increased genetic or familial risk to develop islet autoimmunity and diabetes. For 1,604 children with confirmed positivity, titers of autoantibodies against insulin (IAA), GAD antibodies (GADA), and insulinoma-associated antigen 2 (IA-2A) were harmonized for diabetes risk analyses. RESULTS Survival analysis from time of confirmed positivity revealed markedly different 5-year diabetes risks associated with IAA (n 5 909), GADA (n 5 1,076), and IA-2A (n 5 714), when stratified by quartiles of titer, ranging from 19% (GADA 1st quartile) to 60% (IA-2A 4th quartile). The minimum titer associated with a maximum difference in 5-year risk differed for each autoantibody, corresponding to the 58.6th, 52.4th, and 10.2nd percentile of children specifically positive for each of IAA, GADA, and IA-2A, respectively. Using these autoantibody type-specific titer thresholds in the 1,481 children with all autoantibodies tested, the 5-year risk conferred by single (n 5 954) and multiple (n 5 527) autoantibodies could be stratified from 6 to 75% (P < 0.0001). The thresholds effectively identified children with a ‡50% 5-year risk when considering age-specific autoantibody screening (57–65% positive predictive value and 56–74% sensitivity for ages 1–5 years). Multivariable analysis confirmed the significance of associations between the three autoantibody titers and diabetes risk, informing a childhood risk surveillance strategy. CONCLUSIONS This study defined islet autoantibody type-specific titer thresholds that significantly improved type 1 diabetes risk stratification in children.
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