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Gastrointestinal pirfenidone adverse events in idiopathic pulmonary fibrosis depending on diet: the MADIET clinical trial.
Molina-Molina, M, Shull, JG, Vicens-Zygmunt, V, Rivera-Ortega, P, Antoniou, K, Bonella, F, Renzoni, E, Russell, AM, Maher, TM, Vancheri, A, et al
The European respiratory journal. 2023;(4)
Abstract
Individuals with IPF who follow a MUFA diet report a lower incidence of pirfenidone gastrointestinal adverse events than those that follow a SFA diet, which could explain the different prevalence in GI pirfenidone AEs reported by countries in IPF cohorts https://bit.ly/3LuzAUJ
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The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies.
Manry, J, Bastard, P, Gervais, A, Le Voyer, T, Rosain, J, Philippot, Q, Michailidis, E, Hoffmann, HH, Eto, S, Garcia-Prat, M, et al
Proceedings of the National Academy of Sciences of the United States of America. 2022;(21):e2200413119
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.
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Individual outcome prediction models for patients with COVID-19 based on their first day of admission to the intensive care unit.
Rigo-Bonnin, R, Gumucio-Sanguino, VD, Pérez-Fernández, XL, Corral-Ansa, L, Fuset-Cabanes, M, Pons-Serra, M, Hernández-Jiménez, E, Ventura-Pedret, S, Boza-Hernández, E, Gasa, M, et al
Clinical biochemistry. 2022;:13-21
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Abstract
BACKGROUND Currently, good prognosis and management of critically ill patients with COVID-19 are crucial for developing disease management guidelines and providing a viable healthcare system. We aimed to propose individual outcome prediction models based on binary logistic regression (BLR) and artificial neural network (ANN) analyses of data collected in the first 24 h of intensive care unit (ICU) admission for patients with COVID-19 infection. We also analysed different variables for ICU patients who survived and those who died. METHODS Data from 326 critically ill patients with COVID-19 were collected. Data were captured on laboratory variables, demographics, comorbidities, symptoms and hospital stay related information. These data were compared with patient outcomes (survivor and non-survivor patients). BLR was assessed using the Wald Forward Stepwise method, and the ANN model was constructed using multilayer perceptron architecture. RESULTS The area under the receiver operating characteristic curve of the ANN model was significantly larger than the BLR model (0.917 vs 0.810; p < 0.001) for predicting individual outcomes. In addition, ANN model presented similar negative predictive value than the BLR model (95.9% vs 94.8%). Variables such as age, pH, potassium ion, partial pressure of oxygen, and chloride were present in both models and they were significant predictors of death in COVID-19 patients. CONCLUSIONS Our study could provide helpful information for other hospitals to develop their own individual outcome prediction models based, mainly, on laboratory variables. Furthermore, it offers valuable information on which variables could predict a fatal outcome for ICU patients with COVID-19.
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Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths.
Bastard, P, Gervais, A, Le Voyer, T, Rosain, J, Philippot, Q, Manry, J, Michailidis, E, Hoffmann, HH, Eto, S, Garcia-Prat, M, et al
Science immunology. 2021;(62)
Abstract
Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals <70 years, 2.3% between 70 and 80 years, and 6.3% >80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.
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Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis.
Herranz, C, Mateo, F, Baiges, A, Ruiz de Garibay, G, Junza, A, Johnson, SR, Miller, S, García, N, Capellades, J, Gómez, A, et al
EMBO molecular medicine. 2021;(9):e13929
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Abstract
Inhibition of mTOR is the standard of care for lymphangioleiomyomatosis (LAM). However, this therapy has variable tolerability and some patients show progressive decline of lung function despite treatment. LAM diagnosis and monitoring can also be challenging due to the heterogeneity of symptoms and insufficiency of non-invasive tests. Here, we propose monoamine-derived biomarkers that provide preclinical evidence for novel therapeutic approaches. The major histamine-derived metabolite methylimidazoleacetic acid (MIAA) is relatively more abundant in LAM plasma, and MIAA values are independent of VEGF-D. Higher levels of histamine are associated with poorer lung function and greater disease burden. Molecular and cellular analyses, and metabolic profiling confirmed active histamine signaling and metabolism. LAM tumorigenesis is reduced using approved drugs targeting monoamine oxidases A/B (clorgyline and rasagiline) or histamine H1 receptor (loratadine), and loratadine synergizes with rapamycin. Depletion of Maoa or Hrh1 expression, and administration of an L-histidine analog, or a low L-histidine diet, also reduce LAM tumorigenesis. These findings extend our knowledge of LAM biology and suggest possible ways of improving disease management.