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Prolonged indoleamine 2,3-dioxygenase-2 activity and associated cellular stress in post-acute sequelae of SARS-CoV-2 infection.
Guo, L, Appelman, B, Mooij-Kalverda, K, Houtkooper, RH, van Weeghel, M, Vaz, FM, Dijkhuis, A, Dekker, T, Smids, BS, Duitman, JW, et al
EBioMedicine. 2023;:104729
Abstract
BACKGROUND Post-acute sequela of SARS-CoV-2 infection (PASC) encompass fatigue, post-exertional malaise and cognitive problems. The abundant expression of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase-2 (IDO2) in fatal/severe COVID-19, led us to determine, in an exploratory observational study, whether IDO2 is expressed and active in PASC, and may correlate with pathophysiology. METHODS Plasma or serum, and peripheral blood mononuclear cells (PBMC) were obtained from well-characterized PASC patients and SARS-CoV-2-infected individuals without PASC. We assessed tryptophan and its degradation products by UPLC-MS/MS. IDO2 activity, its potential consequences, and the involvement of the aryl hydrocarbon receptor (AHR) in IDO2 expression were determined in PBMC from another PASC cohort by immunohistochemistry (IHC) for IDO2, IDO1, AHR, kynurenine metabolites, autophagy, and apoptosis. These PBMC were also analyzed by metabolomics and for mitochondrial functioning by respirometry. IHC was also performed on autopsy brain material from two PASC patients. FINDINGS IDO2 is expressed and active in PBMC from PASC patients, as well as in brain tissue, long after SARS-CoV-2 infection. This is paralleled by autophagy, and in blood cells by reduced mitochondrial functioning, reduced intracellular levels of amino acids and Krebs cycle-related compounds. IDO2 expression and activity is triggered by SARS-CoV-2-infection, but the severity of SARS-CoV-2-induced pathology appears related to the generated specific kynurenine metabolites. Ex vivo, IDO2 expression and autophagy can be halted by an AHR antagonist. INTERPRETATION SARS-CoV-2 infection triggers long-lasting IDO2 expression, which can be halted by an AHR antagonist. The specific kynurenine catabolites may relate to SARS-CoV-2-induced symptoms and pathology. FUNDING None.
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[Subtle and subclinical neurological findings in patients with SARS-CoV-2].
Martínez-Piña, DA, San Juan-Orta, D, González-Guevara, E, Vázquez-Díaz, CE, Hernández-González, MA, Sosa-Ramos, JO
Revista medica del Instituto Mexicano del Seguro Social. 2023;(6):767-775
Abstract
BACKGROUND There are severe neurological conditions in patients with COVID-19, such as: cerebrovascular disease, Guillain-Barré syndrome, encephalitis, acute hemorrhagic necrotizing encephalopathy and myelitis. OBJECTIVE We describe that the patient with SARS-CoV 2 with respiratory symptoms has subtle or subclinical neurological manifestations. MATERIAL AND METHODS Observational, cross-sectional, analytical study, which included patients aged 18-65 years with respiratory symptoms and a confirmed diagnosis of COVID-19. Intubated patients with chronic neurodegenerative diseases or pre-existing neurological compromise were excluded. Semiology of the headache and neurological examination were performed; Serum levels of glucose, protein, electrolytes, lactate, C-reactive protein, lactic dehydrogenase, and D-dimer were measured. Cerebrospinal fluid (CSF) analysis and electroencephalogram (EEG) were also performed in patients who accepted the risks. RESULTS A high prevalence of subtle neurological manifestations was found in patients with COVID-19 with only a respiratory clinical picture. Headache, anosmia, dysgeusia, and hypopalesthesia predominated in the early stages, with frequent abnormal findings in the CSF (>70%) and less frequently in the EEG (<20%). CONCLUSIONS Headache, anosmia, dysgeusia and hypoesthesia were frequent at the beginning of the infection, together with abnormal findings in CSF and EEG, without other neurological symptoms or neurological disease.
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NEUROPROTECTIVE AND ANTIOXIDANT POTENTIAL OF MONTELUKAST-ACETYLCYSTEINE COMBINATION THERAPY FOR BRAIN PROTECTION IN PATIENTS WITH COVID-19 INDUCED PNEUMONIA.
Samsonia, M, Kandelaki, M, Baratashvili, N, Gvaramia, L
Georgian medical news. 2023;(335):111-118
Abstract
Direct critical attack of the coronavirus on the alveoli and the excessive release of a large number of cytokines (IL-6, IL-1, TNF-α, etc.) provides suitable conditions for the further development of acute respiratory distress syndrome (ARDS) and severe acute respiratory failure. Serious decrease in blood oxygenation often lead to the deterioration of macro- and microcirculation, irreversible brain damage and hence, persistent neurological and mental disorders despite background intensive therapy and adequate respiratory support. Therefore, the aim of our open prospective observational study was to investigate the neuroprotective and antioxidant effectiveness of montelukast-acetylcysteine combination therapy for brain protection in patients with COVID-19 viral pneumonia. A study was performed for five hundred seventy-eight (n=578) outpatients who were tested positive for novel coronavirus (SARS-CoV-2) by nasopharyngeal swap. The median age of patients was 62±17.45 years. In addition to clinical features and RT-PCR results, chest CT and chest X-ray (CXR) with high sensitivity were also very helpful for the early identification of viral pneumonia and COVID-19 disease assessment. Considering the severity of Covid-19 pneumonia and the level of arterial oxygen saturation (transcutaneous hemoglobin oxygen saturation) on room air, all patients were divided into three major groups. Group 1 (n=288) consisted of patients with a mild shift in oxygen saturation (SpO2 ≥ 95%) and well-defined pulmonary lesions (within 1-2 segments) without concomitant diseases; the second group (Group 2, n=250) included patients with clinical manifestations of moderate severity associated with a current saturation of 90-95% (SpO2) and small pulmonary lesions on chest X-ray in the presence of concomitant diseases: arterial hypertension (stage III) or CHF (FC/NYHA-2), coronary heart disease or type 2 diabetes, cancer, tuberculosis, etc. Most of the patients in third group (Group 3, n=48), during imaging studies, showed bilateral lung affection with low and peripheral distribution (with both - either ground glass opacities or multiple pulmonary nodules) and cardiomegaly. The respiratory failure of stage II-III (current oxygen saturation SpO2 75-90%), high respiratory rate (≥25 per minute), hemodynamic impairment (BP≤100/60 mm Hg. Art., heart rate ≥125/min) were the most common objective clinical findings seen in this subset of patients. Laboratory changes included leukopenia less than 4.0x109/L or leukocytosis (≥10.0X109/L). Background respiratory support with low-flow oxygen therapy and combined pharmacotherapy, where, along with montelukast and acetylcysteine, patients were prescribed a cephalosporin, a fluoroquinolone, an antifungal drug, a histamine blocker, an antiplatelet agent, a complex of B vitamins, led to a significant improvement in symptoms and laboratory parameters during the course of the disease. The mean values of the blood biomarkers (CRP - 21.46±4.43 mg/l, LDH - 410.71±40.63 U/l, procalcitonin - 1.08±0.31 ng/ml, and ferritin - 270.43±27.23 ng/ml) return to normal by the 20th day after the fever subsides. Laboratory parameters before and after treatment course showed statistically significant differences between variables (p<0.05). No patient in Group 3 received JAK inhibitors (tofacitinib and baricitinib), IL-6 (olokizumab), IL-17A (netakimab) and glucocorticosteroids, however, recovery rates were completely good. Assessment of the patient's neurological status (based on the NIHSS scores) revealed no signs of neurological changes. Thus, based on the data given, it can be concluded that the high efficacy of the acetylcysteine/montelukast combination (as neuroprotectors) in pneumonia caused by COVID-19 is due to the effect of drugs on key mechanisms of pathogenesis: reduction of oxidative stress as drugs (combination) ensuring the free radical scavenging; stimulation of glutathione synthesis; suppression of cytokine storm; reduction of bronchospasm, mucus secretion and airway edema; lowering of BBB permeability and the ability to improve cerebral microcirculatory perfusion in the presence of antiplatelet agents. In conclusion, the combination of montelukast and acetylcysteine may provide an effective, safe, multicomponent approach to the prevention of hypoxic brain injury in patients with COVID-19 pneumonia.
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A combined role for low vitamin D and low albumin circulating levels as strong predictors of worse outcome in COVID-19 patients.
Sanson, G, De Nicolò, A, Zerbato, V, Segat, L, Koncan, R, Di Bella, S, Cusato, J, di Masi, A, Palermo, A, Caironi, P, et al
Irish journal of medical science. 2023;(1):423-430
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PURPOSE We aimed to assess the combined role of vitamin D and albumin serum levels as predictors of COVID-19 disease progression. METHODS We conducted a prospective observational study on adult patients hospitalized for SARS-CoV-2 pneumonia (March-September 2020). Vitamin D and albumin serum levels were measured on admission. These variables were categorized in albumin < 3.5 or ≥ 3.5 g/dL and vitamin D < 30 ng/mL or ≥ 30 ng/mL. We excluded patients with known bone diseases, renal failure, hypercalcemia and/or treated with antiepileptic drugs and steroids, and patients who received previous vitamin D supplementation. A composite outcome including any ventilatory support, PaO2/FiO2 ratio, and 60-day mortality was defined. RESULTS Sixty-nine patients were enrolled, of whom 50% received non-invasive (NIV) or invasive mechanical ventilation (IMV), 10% died, whereas 89% and 66% presented low albumin and low vitamin D serum levels, respectively. No correlation between vitamin D and albumin levels was found. In multivariable logistic regression analyses adjusted for sex and age-corrected comorbidities, patients having albumin < 3.5 g/dL and vitamin D < 30 ng/mL showed a significant increased risk for all study outcomes, namely NIV/IMV (OR 3.815; 95% CI 1.122-12.966; p = 0.032), NIV/IMV or death (OR 3.173; 95% CI 1.002-10.043; p = 0.049) and PaO2/FIO2 ≤ 100 (OR 3.410; 95% CI 1.138-10.219; p = 0.029). CONCLUSION The measurement of both vitamin D and serum albumin levels on COVID-19 patients' admission, and their combined evaluation, provides a simple prognostic tool that could be employed to guide prompt clinical decisions.
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Short-term complications and post-acute sequelae in hospitalized paediatric patients with COVID-19 and obesity: A multicenter cohort study.
Valenzuela, G, Alarcón-Andrade, G, Schulze-Schiapacasse, C, Rodríguez, R, García-Salum, T, Pardo-Roa, C, Levican, J, Serrano, E, Avendaño, MJ, Gutiérrez, M, et al
Pediatric obesity. 2023;(2):e12980
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BACKGROUND Obesity increases the severity of coronavirus disease 2019 illness in adults. The role of obesity in short-term complications and post-acute sequelae in children is not well defined. OBJECTIVE To evaluate the relationship between obesity and short-term complications and post-acute sequelae of SARS-CoV-2 infection in hospitalized paediatric patients. METHODS An observational study was conducted in three tertiary hospitals, including paediatric hospitalized patients with a confirmatory SARS-CoV-2 RT-PCR from March 2020 to December 2021. Obesity was defined according to WHO 2006 (0-2 years) and CDC 2000 (2-20 years) growth references. Short-term outcomes were intensive care unit admission, ventilatory support, superinfections, acute kidney injury, and mortality. Neurological, respiratory, and cardiological symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms were considered as post-acute sequalae. Adjusted linear, logistic regression and generalized estimating equations models were performed. RESULTS A total of 216 individuals were included, and 67 (31.02%) of them had obesity. Obesity was associated with intensive care unit admission (aOR = 5.63, CI95% 2.90-10.94), oxygen requirement (aOR = 2.77, CI95% 1.36-5.63), non-invasive ventilatory support (aOR = 6.81, CI95% 2.11-22.04), overall superinfections (aOR = 3.02 CI95% 1.45-6.31), and suspected bacterial pneumonia (aOR = 3.00 CI95% 1.44-6.23). For post-acute sequalae, obesity was associated with dyspnea (aOR = 9.91 CI95% 1.92-51.10) and muscle weakness (aOR = 20.04 CI95% 2.50-160.65). CONCLUSIONS In paediatric hospitalized patients with COVID-19, severe short-term outcomes and post-acute sequelae are associated with obesity. Recognizing obesity as a key comorbidity is essential to develop targeted strategies for prevention of COVID-19 complications in children.
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Persistent CD8+ T cell proliferation and activation in COVID-19 adult survivors with post-acute sequelae: a longitudinal, observational cohort study of persistent symptoms and T cell markers.
LaVergne, SM, Dutt, TS, McFann, K, Baxter, BA, Webb, TL, Berry, K, Tipton, M, Stromberg, S, Sullivan, BM, Dunn, J, et al
Frontiers in immunology. 2023;:1303971
Abstract
INTRODUCTION Post-acute sequelae of COVID-19 affects the quality of life of many COVID-19 survivors, yet the etiology of post-acute sequelae of COVID-19 remains unknown. We aimed to determine if persistent inflammation and ongoing T-cell activation during convalescence were a contributing factor to the pathogenesis of post-acute sequelae of COVID-19. METHODS We evaluated 67 individuals diagnosed with COVID-19 by nasopharyngeal polymerase chain reaction for persistent symptoms during convalescence at separate time points occurring up to 180 days post-diagnosis. Fifty-two of these individuals were evaluated longitudinally. We obtained whole blood samples at each study visit, isolated peripheral blood mononuclear cells, and stained for multiple T cell activation markers for flow cytometry analysis. The activation states of participants' CD4+ and CD8+ T-cells were next analyzed for each of the persistent symptoms. RESULTS Overall, we found that participants with persistent symptoms had significantly higher levels of inflammation at multiple time points during convalescence when compared to those who fully recovered from COVID-19. Participants with persistent dyspnea, forgetfulness, confusion, and chest pain had significantly higher levels of proliferating effector T-cells (CD8+Ki67+), and those with chest pain, joint pain, difficulty concentrating, and forgetfulness had higher levels of regulatory T-cells (CD4+CD25+). Additionally, those with dyspnea had significantly higher levels of CD8+CD38+, CD8+ Granzyme B+, and CD8+IL10+ cells. A retrospective comparison of acute phase inflammatory markers in adults with and without post-acute sequelae of COVID-19 showed that CD8+Ki67+ cells were significantly higher at the time of acute illness (up to 14 days post-diagnosis) in those who developed persistent dyspnea. DISCUSSION These findings suggest continued CD8+ T-cell activation following SARS-CoV-2 infection in adults experiencing post-acute sequelae of COVID-19 and that the increase in T regulatory cells for a subset of these patients represents the ongoing attempt by the host to reduce inflammation.
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Long-term outcomes in critically ill patients who survived COVID-19: The NUTRICOVID observational cohort study.
Álvarez-Hernández, J, Matía-Martín, P, Cáncer-Minchot, E, Cuerda, C, ,
Clinical nutrition (Edinburgh, Scotland). 2023;(10):2029-2035
Abstract
BACKGROUND & AIMS Malnutrition and sarcopenia may last beyond hospital discharge, especially in patients admitted to intensive care units (ICU), having a negative impact on patient recovery and leading to disability, poor quality of life, and additional morbidity. No prior evidence is available for post-ICU management and follow-up of coronavirus disease 2019 (COVID-19) patients and their long-term evolution. This study reports on the one-year-long evolution of a cohort of COVID-19 survivors after ICU discharge, in terms of nutritional and functional status as well as health-related quality of life (HRQoL). METHODS A multicenter, ambispective, observational cohort study (NUTRICOVID study) was conducted in 16 public hospitals located in the Community of Madrid with COVID-19 survivors who were admitted to ICU during the first outbreak. Retrospective and prospective data were collected from hospital admission to one year after discharge. At hospital discharge and at 3, 6 and 12 months post-discharge, the following outcomes were recorded: weight, risk of malnutrition (MUST) and sarcopenia (SARC-F), medical nutrition therapy (MNT), functional status (Barthel index), and HRQoL (EQ-5D-5L). RESULTS A total of 199 patients (70.4% male, mean age [SD] of 60.7 [10.1]) were included in the study. At hospital discharge, mean weight loss was 16.4% (8.0%), whereas most patients gained weight after discharge with an increase of 16.5% (14.0%) at 12 months. The proportion of patients at high risk of malnutrition decreased from 83.2% at hospital discharge to 2.1% at 12 months. The proportion at risk of sarcopenia decreased from 86.9% at hospital discharge to 13.4% at 12 months. At hospital discharge, 69 patients received MNT by means of oral nutritional supplements (ONS) while two patients required enteral nutrition (EN). At 12 months, only 12 patients continued taking ONS, with no patients taking EN. Regarding functional status, 72.9% of patients were moderately or severely dependent at hospital discharge, whereas 87.2% showed low dependency or independency after 12 months. The EQ-VAS values increased from hospital discharge (39 [21.2]) to 6 months post-discharge and remained steady up to 12 months (72.7 [19.0]). The mean health value improved from hospital discharge (0.25 [0.41]) to 6 months post-discharge (0.80 [0.24]) and was maintained thereafter. CONCLUSIONS Patients' nutritional and functional impairment at hospital discharge was high, with high dependency status and low HRQoL; however, their situation improved progressively during the 12 months following hospital discharge. Nevertheless, there is a need to define early strategies to optimize the nutritional and functional recovery of COVID-19 patients.
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Developmental and behavioural outcomes at 2 years in babies born during the COVID-19 pandemic: communication concerns in a pandemic birth cohort.
Byrne, S, Sledge, H, Hurley, S, Hoolahan, S, Franklin, R, Jordan, N, Boland, F, Murray, DM, Hourihane, J, ,
Archives of disease in childhood. 2023;(10):846-851
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INTRODUCTION The CORAL (Impact of Corona Virus Pandemic on Allergic and Autoimmune Dysregulation in Infants Born During Lockdown) study reported a reduction in social communication milestones in 12-month-old infants born into the COVID-19 pandemic. AIMS To look at 24-month developmental and behavioural outcomes in the CORAL cohort. DESIGN The CORAL study is a longitudinal prospective observational study of Irish infants born in the first 3 months of the pandemic. At 24 months of age, the Ages and Stages Developmental Questionnaire (ASQ24) and the Child Behaviour Checklist (CBCL) were completed and compared with prepandemic BASELINE (Babies After SCOPE Evaluating the Longitudinal Impact Using Neurological and Nutritional Impact) cohort. RESULTS 917 babies (312 CORAL infants and 605 BASELINE infants) were included. At 24 months of age, infants in the CORAL and BASELINE cohorts had similar developmental ASQ24 scores in fine motor, problem solving and personal and social domains but ASQ24 communication scores were significantly lower in the CORAL group compared with the BASELINE cohort (mean (SD) 49.5 (15.1) vs 53.7 (11.6), p<0.01). Infants from the CORAL cohort were more likely to score below standardised cut-offs for developmental concern in the communication domain (11.9% CORAL compared with 5.4% BASELINE, p<0.01). Unadjusted ASQ24 gross motor scores were lower for the pandemic cohort. Fewer CORAL infants fell under 2 SD cut-off in personal-social subdomain. For CBCL, there was no evidence of difference in scores between the cohorts on multivariable analysis. CONCLUSION 24-month-old pandemic-born infants had largely similar developmental and behavioural scores compared with their prepandemic counterparts. Concerns have been raised in the communication developmental domain.
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[Estilo de vida, hábitos de higiene oral y autopercepción del estado anímico en estudiantes de Odontología de la Comunidad de Madrid durante la pandemia de la COVID-19: ¿pudo la pandemia tener algún efecto favorable?].
Descalzo-Casado, E, Martín Morales, JF, Arias-Macias, CM, Romero-Lastra, PT, Kobayashi, H, Casado-Gómez, I
Revista espanola de salud publica. 2023
Abstract
OBJECTIVE The COVID-19 pandemic and its control measures seem to have altered the vital dynamics of the population. It was justifiable, therefore, to try to specify the impact on lifestyle, oral hygiene and mood, in specific groups, such as dental university students in Madrid, who were accessible to us. METHODS An anonymous and voluntary cross-sectional observational study was carried out in the first fortnight of December 2021, through an ad hoc online questionnaire, in dentistry students from the Autonomous Community of Madrid. Descriptive analysis of the variables was performed and the associations and significance were assessed using Chi-square and T-student. RESULTS There were received seventy-two surveys. 82% were women and 18% men, with 23±3 years of mean age. 94% had good oral hygiene habits that improved with the pandemic. Their usual diet was varied and complete. Women consumed less meat (p=0.014) and more fruit (p=0.066), habits that they maintained, and men have improved with an increase in fruits (p<0.002), vegetables and legumes (p<0.003) in the pandemic. Tobacco (23,4%) and alcohol (54%) consumption decreased in confinement and increase in post-confinement. 36% increased their physical activity, initially low, especially in post-confinement. CONCLUSIONS The students in the sample have good oral hygiene and eating habits, which they keep and even improve with the pandemic, including an increase in physical exercise in a significant fraction of the sample. The confinement affect the mood and social relationships, even altering the sleep of women, with an increase in night awakenings, especially in post-confinement.
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The three facets of the SARS-CoV-2 pandemic during the first two waves in the northern, central, and southern Italy.
Buscemi, S, Davoli, C, Trecarichi, EM, Morrone, HL, Tassone, B, Buscemi, C, Randazzo, C, Barile, AM, Colombrita, P, Soresi, M, et al
Journal of infection and public health. 2023;(4):520-525
Abstract
BACKGROUND There is a scarcity of information in literature regarding the clinical differences and comorbidities of patients affected by Coronavirus disease 2019 (COVID-19), which could clarify the different prevalence of the outcomes (composite and only death) between several Italian regions. OBJECTIVE This study aimed to assess the heterogeneity of clinical features of patients with COVID-19 upon hospital admission and disease outcomes in the northern, central, and southern Italian regions. METHODS An observational cohort multicenter retrospective study including 1210 patients who were admitted for COVID-19 in Infectious diseases, Pulmonology, Endocrinology, Geriatrics and Internal Medicine Units in Italian cities stratified between north (263 patients); center (320 patients); and south (627 patients), during the first and second pandemic waves of SARS-CoV-2 (from February 1, 2020 to January 31, 2021). The data, obtained from clinical charts and collected in a single database, comprehended demographic characteristics, comorbidities, hospital and home pharmacological therapies, oxygen therapy, laboratory values, discharge, death and Intensive care Unit (ICU) transfer. Death or ICU transfer were defined as composite outcomes. RESULTS Male patients were more frequent in the northern Italian region than in the central and southern regions. Diabetes mellitus, arterial hypertension, chronic pulmonary and chronic kidney diseases were the comorbidities more frequent in the southern region; cancer, heart failure, stroke and atrial fibrillation were more frequent in the central region. The prevalence of the composite outcome was recorded more frequently in the southern region. Multivariable analysis showed a direct association between the combined event and age, ischemic cardiac disease, and chronic kidney disease, in addition to the geographical area. CONCLUSIONS Statistically significant heterogeneity was observed in patients with COVID-19 characteristics at admission and outcomes from northern to southern Italy. The higher frequency of ICU transfer and death in the southern region may depend on the wider hospital admission of frail patients for the availability of more beds since the burden of COVID-19 on the healthcare system was less intense in southern region. In any case, predictive analysis of clinical outcomes should consider that the geographical differences that may reflect clinical differences in patient characteristics, are also related to access to health-care facilities and care modalities. Overall, the present results caution against generalizability of prognostic scores in COVID-19 patients derived from hospital cohorts in different settings.