Peripheral microcirculatory alterations are associated with the severity of acute respiratory distress syndrome in COVID-19 patients admitted to intermediate respiratory and intensive care units

COVID-19; Endothelial dysfunction; MicrocirculationCOVID-19; Disfunción endotelial; MicrocirculaciónCOVID-19; Disfunció endotelial; MicrocirculacióBackground COVID-19 is primarily a respiratory disease; however, there is also evidence that it causes endothelial damage in the microvasculature of several organs. The aim of the present study is to characterize in vivo the microvascular reactivity in peripheral skeletal muscle of severe COVID-19 patients. Methods This is a prospective observational study carried out in Spain, Mexico and Brazil. Healthy subjects and severe COVID-19 patients admitted to the intermediate respiratory (IRCU) and intensive care units (ICU) due to hypoxemia were studied. Local tissue/blood oxygen saturation (StO2) and local hemoglobin concentration (THC) were non-invasively measured on the forearm by near-infrared spectroscopy (NIRS). A vascular occlusion test (VOT), a three-minute induced ischemia, was performed in order to obtain dynamic StO2 parameters: deoxygenation rate (DeO2), reoxygenation rate (ReO2), and hyperemic response (HAUC). In COVID-19 patients, the severity of ARDS was evaluated by the ratio between peripheral arterial oxygen saturation (SpO2) and the fraction of inspired oxygen (FiO2) (SF ratio). Results Healthy controls (32) and COVID-19 patients (73) were studied. Baseline StO2 and THC did not differ between the two groups. Dynamic VOT-derived parameters were significantly impaired in COVID-19 patients showing lower metabolic rate (DeO2) and diminished endothelial reactivity. At enrollment, most COVID-19 patients were receiving invasive mechanical ventilation (MV) (53%) or high-flow nasal cannula support (32%). Patients on MV were also receiving sedative agents (100%) and vasopressors (29%). Baseline StO2 and DeO2 negatively correlated with SF ratio, while ReO2 showed a positive correlation with SF ratio. There were significant differences in baseline StO2 and ReO2 among the different ARDS groups according to SF ratio, but not among different respiratory support therapies. Conclusion Patients with severe COVID-19 show systemic microcirculatory alterations suggestive of endothelial dysfunction, and these alterations are associated with the severity of ARDS. Further evaluation is needed to determine whether these observations have prognostic implications. These results represent interim findings of the ongoing HEMOCOVID-19 trial. Trial registration ClinicalTrials.gov NCT04689477. Retrospectively registered 30 December 2020.The study has received funding from Fundació CELLEX Barcelona, Fundació Mir-Puig, Ajuntament de Barcelona, Agencia Estatal de Investigación (PHOTOMETABO, PID2019-106481RB-C31/10.13039/501100011033), the "Severo Ochoa" Programme for Centers of Excellence in R&D (CEX2019-000910-S), the Obra social “La Caixa” Foundation (LlumMedBcn), Generalitat de Catalunya (CERCA, AGAUR-2017-SGR-1380, RIS3CAT-001-P-001682 CECH), European Commission Horizon 2020 (FEDER, 688303/LUCA, 101016087/VASCOVID, 87114/LASERLAB-EUROPE V). We also acknowledge the collaboration and an instrument loan from Artinis (Netherlands)

Oxaliplatin-Related Ocular Toxicity

We report the case of a 52-year-old woman with advanced colorectal cancer who was treated with oxaliplatin on a FOLFOX schedule. After 3 cycles of chemotherapy, she started to complain of visual loss, altered color vision and neurological symptoms. Due to the suspicion of ocular and neurological toxicity, antineoplastic treatment was stopped. Her visual field showed a concentric bilateral scotoma and the electrooculogram test revealed severe impairment of the retinal pigment epithelium. Visual acuity, color vision and visual field recovered completely 8 months later, although electrooculogram remained abnormal. Ocular toxicity has been reported as an infrequent adverse event of oxaliplatin. Findings in this case indicate toxicity of this chemotherapeutic agent on the retinal pigment epithelium, which has not been reported before. This damage could be permanent, and it thus differs from previously described oxaliplatin-induced ocular toxicities, which are usually transient and reversible. With increasing use of oxaliplatin as first-line treatment in advanced colorectal cancer, we have to be aware of this possible toxicity

Predictors for functional and anatomic outcomes in macular edema secondary to non-infectious uveitis

Aims We aimed to investigate predictive factors for visual and anatomic outcomes in patients with macular edema secondary to non-infectious uveitis. Material and methods We conducted a multicenter, prospective, observational, 12-month follow-up study. Participants included in the study were adults with non-infectious uveitic macular edema (UME), defined as central subfoveal thickness (CST) of > 300 mu m as measured by spectral domain optical coherence tomography (SD-OCT) and fluid in the macula. Demographic, clinical and tomographic data was recorded at baseline, 1, 3, 6 and 12 months. Foveal-centered SD-OCT exploration was set as the gold-standard determination of UME using a standard Macular Cube 512x128 A-scan, within a 6 x 6 mm(2) area, and the Enhanced High Definition Single-Line Raster. To assess favorable prognosis, the main outcomes analyzed were the best-corrected visual acuity (BCVA) and the CST. Favorable prognosis was defined as sustained improvement of BCVA (2 lines of gain of the Snellen scale) and CST (decrease of 20% of the initial value or < 300 mu m) within a 12 month period. Results Fifty-six eyes were analyzed. The number of eyes with sustained improvement in the CST was 48 (86.2%), against 23 (41.1%) eyes with sustained improvement in BCVA. Favorable prognosis, as defined above, was observed in 18 (32.1%) eyes. UME prognosis was negatively correlated with baseline foveal thickening, alteration in the vitreo-macular interface and cystoid macular edema. In contrast, bilaterally, systemic disease and the presence of anterior chamber cells were predictive of favorable prognosis. Conclusion Available treatment modalities in UME may avoid chronic UME and improve anatomic outcome. However, the proportion of functional amelioration observed during 12 months of follow-up is lower. Thicker CST, alteration in the vitreo-macular interface and cystoid macular edema may denote less favorable prognosis. Conversely, bilaterally, systemic disease and anterior chamber cells may be associated with favorable prognosis in UME.This work was supported by grants from: Spanish Ministry of Economy, Industry and Competitivity, Carlos III Health Institute, cofinanced by the European Regional Development Fund, identification number: PI13/02148, Principal Investigator: AA; http://www.eng.isciii.es/ISCIII/es/contenidos/fd-investigacion/financiacion.shtml.The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Golimumab as rescue therapy for refractory immune-mediated uveitis: a three-center experience

OBJECTIVE: To evaluate, in three Spanish tertiary referral centres, the short-term safety and efficacy of golimumab (GLM) for treatment of immune-mediated uveitis resistant to previous immunosuppressive therapy. METHODS: Nonrandomized retrospective interventional case series. Thirteen patients with different types of uveitis that were resistant to treatment with at least 2 previous immunosuppressors were included in this study. All included patients were treated with GLM (50 mg every four weeks) during at least 6 months. Clinical evaluation and treatment-related side effects were assessed at least four times in all included patients. RESULTS: Eight men and 5 women (22 affected eyes) with a median age of 30 years (range 20-38) and active immune-mediated uveitides were studied. GLM was used in combination with conventional immunosuppressors in 7 patients (53.8%). GLM therapy achieved complete control of inflammation in 12/13 patients (92.3%) after six months of treatment. There was a statistically significant improvement in mean BCVA (0.60 versus 0.68, P = 0.009) and mean 1 mm central retinal thickness (317 versus 261.2 µ, P = 0.05) at the six-month endpoint when compared to basal values. No major systemic adverse effects associated with GLM therapy were observed. CONCLUSIONS: GLM is a new and promising therapeutic option for patients with severe and refractory uveitis

Proinflammatory cytokines and C-reactive protein in uveitis associated with Behçet's disease

The aim of the present study was to determine the serum cytokine profile and levels of high sensitivity C-reactive protein (hsCRP) in patients with uveitis associated with Behcet's disease (BD) and to compare them with those obtained from healthy control subjects. We determined the serum concentration of interferon-gamma (IFN-gamma), interleukin-1 beta (IL-1 beta), IL-12p70, IL-17A, tumor necrosis factor-alpha (TNF-alpha), and hsCRP in 13 patients with active uveitis associated to BD, 24 inactive BD patients, and 20 controls. In a subgroup of 10 active patients, a second serum sample was obtained when the disease was inactive. Cytokine profiles and hsCRP levels were correlated with disease activity, severity, complications, and visual outcome. Levels of IFN-gamma and TNF-alpha were significantly increased in patients with active uveitis associated to BD compared to controls (P < 0.05). IFN-gamma, TNF-alpha, and hsCRP were significantly higher during active uveitis associated to BD compared to inactive disease (P < 0.05). Furthermore, IL-17A was significantly increased in patients with active BD without pharmacological treatment compared to controls (P < 0.05). No significant correlations were found with specific cytokine profiles and disease severity, visual outcome, or complications. In summary, increased serum levels of IFN-gamma, TNF-alpha, IL-17A, and hsCRP were associated with active uveitis associated with BD and might serve as markers of disease activity

Anti-TNF-a therapy in refractory uveitis associated with sarcoidosis: multicenter study of 17 patients

OBJECTIVES: To assess anti-TNF-α therapy response in uveitis associated with sarcoidosis refractory to conventional immunosuppressive therapy. METHODS: Open-label, multicenter, retrospective study on patients with sarcoid uveitis who underwent anti-TNF-α therapy because of inadequate response to conventional therapy including corticosteroids and at least 1 systemic synthetic immunosuppressive drug. The main outcome measurements were degree of anterior and posterior chamber inflammation, visual acuity, macular thickness, and immunosuppression load. RESULTS: A total of 17 patients (8 men; 29 affected eyes; mean ± standard deviation age 38.4 ± 16.8; range: 13-76 years) were studied. The patients had bilateral hilar lymphadenopathy (58.8%), lung parenchyma involvement (47.1%), peripheral lymph nodes (41.2%), and involvement of other organs (52.9%). Angiotensin-converting enzyme was elevated in 58.8%. The most frequent ocular pattern was bilateral chronic relapsing panuveitis. The first biologic agent used was adalimumab in 10 (58.8%) and infliximab in 7 (41.2%) cases. Infliximab 5mg/kg intravenously every 4-8 weeks and adalimumab 40mg subcutaneously every 2 weeks were the most common administration patterns. In most cases anti-TNF-α therapy was given in combination with immunosuppressive drugs. The mean duration of follow-up was 33.9 ± 17.1 months. Significant improvement was observed following anti-TNF-α therapy. Baseline results versus results at 2 years from the onset of biologic therapy were the following: the median of cells in the ocular anterior chamber [interquartile range-IQR] 0.5 [0-2] versus 0 [0-0] (p = 0.003), vitritis 0 [0-1.25] versus 0 [0-0] (p = 0.008), macular thickness (391.1 ± 58.8 versus 247 ± 40.5µm) (p = 0.028), and visual acuity 0.60 ± 0.33 versus 0.74 ± 0.27; p = 0.009. The median daily [interquartile range] dose of prednisone was also reduced from 10 [0-30]mg at the onset of the anti-TNF-α therapy to 0 [0-0]mg at 2 years (p = 0.02). Significant reduction was also achieved in the immunosuppressive load. CONCLUSION: Anti-TNF-α therapy is effective in sarcoid uveitis patients refractory to conventional immunosuppressive therapy. Infliximab and adalimumab allowed a substantial reduction in prednisone dose despite having failed standard therapy.Funding: This work was also partially supported by RETICS Programs, RD08/0075 (RIER) and RD12/0009/0013 from ‘‘Instituto de Salud Carlos III’’ (ISCIII) (Spain) Acknowledgments: This work was partially supported by RETICS Program, RD12/0009/0013 (RIER) from “Instituto de Salud Carlos III” (ISCIII) (Spain)

Comparative Study of Infliximab Versus Adalimumab in Refractory Uveitis Due to Behçet's Disease: National Multicenter Study of 177 Cases

Objective: To compare the efficacy of infliximab (IFX) versus adalimumab (ADA) as a first-line biologic drug over 1 year of treatment in a large series of patients with refractory uveitis due to Behçet's disease (BD). Methods: We conducted an open-label multicenter study of IFX versus ADA for BD-related uveitis refractory to conventional nonbiologic treatment. IFX or ADA was chosen as the first-line biologic agent based on physician and patient agreement. Patients received 3-5 mg/kg intravenous IFX at 0, 2, and 6 weeks and every 4-8 weeks thereafter, or 40 mg subcutaneous ADA every other week without a loading dose. Ocular parameters were compared between the 2 groups. Results: The study included 177 patients (316 affected eyes), of whom 103 received IFX and 74 received ADA. There were no significant baseline differences between treatment groups in main demographic features, previous therapy, or ocular sign severity. After 1 year of therapy, we observed an improvement in all ocular parameters in both groups. However, patients receiving ADA had significantly better outcomes in some parameters, including improvement in anterior chamber inflammation (92.31% versus 78.18% for IFX; P = 0.06), improvement in vitritis (93.33% versus 78.95% for IFX; P = 0.04), and best-corrected visual acuity (mean ± SD 0.81 ± 0.26 versus 0.67 ± 0.34 for IFX; P = 0.001). A nonsignificant difference was seen for macular thickness (mean ± SD 250.62 ± 36.85 for ADA versus 264.89 ± 59.74 for IFX; P = 0.15), and improvement in retinal vasculitis was similar between the 2 groups (95% for ADA versus 97% for IFX; P = 0.28). The drug retention rate was higher in the ADA group (95.24% versus 84.95% for IFX; P = 0.042). Conclusion: Although both IFX and ADA are efficacious in refractory BD-related uveitis, ADA appears to be associated with better outcomes than IFX after 1 year of follow-up

Parents'diet quality and physical activity are associated with lifestyle in spanish children and adolescents: the PASOS study

Background: Non-communicable chronic diseases are associated with a low-quality diet, low physical activity, and sedentary behavior. Objective: To assess how parents’ diet and physical activity habits were associated with their offsprings’ lifestyles. Study design: A cross-sectional analysis of 8–16-year-old children and adolescents (n = 2539; 51.9% girls) was carried out within the frame of the first edition of the Physical Activity, Sedentarism, Lifestyles, and Obesity in Spanish Youth study (PASOS-2019). Data on adherence to the Mediterranean Diet (MedDiet), daily moderate–vigorous physical activity (MVPA), and screen time per day (television, computer, video games, and mobile phone) were collected from children and adolescents, and data on parents’ diet quality and physical activity were compiled. Logistic regression models were used to assess the association between parents’ lifestyles and those of children and adolescents. Results: High diet quality of parents was associated with higher adherence to the MedDiet of children and adolescents, as well as high consumption of fruit, vegetables, fish, nuts, and legumes. The high physical activity level of parents was associated with the low consumption of fast foods, sweets, and candies in children and adolescents. Children with high levels of physical activity were those whose parents showed better diet quality and physical activity levels. Conclusions: Parents’ high diet quality and physical activity were associated with healthy lifestyles, higher adherence to the MedDiet, and physical activity of their offspring, mainly in adolescents.The PASOS study was funded by Fundación PROBITAS and the Gasol Foundation. Additional funds were received from the FC Barcelona Foundation, Banco Santander, IFA, Vienna, and the Fundación Deporte Joven (no references are applicable). M.M.M., M.R.M., M.G.G., J.A.T. and C.B. were funded by CIBEROBN (CB12/03/30038), and M.M. and I.L. (CB22/03/00058) by the Institute of Health Carlos III (ISCIII), and co-funded by the European Regional Development Fund

Modelling Macular Edema:The Effect of IL-6 and IL-6R Blockade on Human Blood-Retinal Barrier Integrity In Vitro

Purpose: Macular edema (ME) is a leading cause of visual loss in a range of retinal diseases and despite the use of antivascular endothelial growth factor (anti-VEGF) agents, its successful treatment remains a major clinical challenge. Based on the indirect clinical evidence that interleukin-6 (IL-6) is a key additional candidate mediator of ME, we interrogated the effect of IL-6 on blood–retinal barrier (BRB) integrity in vitro. Methods: Human retinal pigment epithelial cell (ARPE-19) and human retinal microvascular endothelial cell (HRMEC) monolayers were used to mimic the outer and inner BRB, respectively. Their paracellular permeability was assessed by measuring the passive permeation of 40 kDa fluorescein isothiocyanate (FITC)-dextran across confluent cells in the presence of IL-6. Transendothelial/epithelial electrical resistance (TEER) then was measured and the distribution of the tight junction protein ZO-1 was assessed by immunofluorescence using confocal microscopy. Results: Treatment with IL-6 for 48 hours significantly increased the diffusion rate of FITC-dextran, decreased TEER, and disrupted the distribution of ZO-1 in ARPE-19 cells, which constitutively express the IL-6 transmembrane receptor, and this was reversed with IL-6R blockade. In contrast, IL-6 did not affect the paracellular permeability, TEER, or ZO-1 distribution in HRMECs. Conclusions: These in vitro data support the hypothesis that IL-6 reversibly disrupts the integrity of ARPE-19 cells, but it does not affect HRMECs. Translational Relevance: IL-6 is a candidate therapeutic target in the treatment of outer BRB driven ME