Chlorpheniramine Intranasal Spray to Accelerate COVID-19 Clinical Recovery in an Outpatient Setting: The ACCROS Trials (preprint)

Purpose: Our group demonstrated the safety, efficacy, and antiviral effect of intranasally administered Chlorpheniramine Maleate (CPM) for treating coronavirus disease 2019 (COVID-19). Since the nasal cavity is the portal of entry for COVID pathogens, sensory and upper respiratory symptoms (URS) (e.g., cough, ageusia, anosmia, nasal congestion, etc.) are significant symptoms in the course of the disease. Intranasal therapies could alleviate the disease-induced URS faster. This study evaluated the effectiveness and safety of intranasal CPM for treating mild to moderate COVID-19-induced URS in the outpatient setting. Methods: The two-part Accelerating COVID-19 Clinical Recovery in an Outpatient Setting (ACCROS) research study was conducted to collect evidence from a randomized, double-blinded placebo-controlled trial (ACCROS-I). Both parts enrolled patients with mild to moderate COVID-19 confirmed by reverse transcription-polymerase chain reaction. The primary endpoint in ACCROS-I was time to clinical recovery, defined as the change from baseline to day 7 in COVID-19 symptoms reported as the percent change (Δ%) in the daily symptoms score (DSS) and the severity of the disease symptoms using a visual analog scale (VAS), on a scale of 1-10 (10=worst symptoms). COVID-19 patients (n = 101) were recruited and assigned to either a 10-day CPM treatment (n=61) or placebo (PLB) (n=40) in addition to standard of care (SoC). Secondary endpoints included the incidence of hospitalization and the proportion of patients with URS on day 7. ACCROS-II data were collected from medical records of COVID-positive subjects using a standardized form. Cohorts of patients treated with CPM and SoC (CPM+Soc) were compared for the duration of general symptoms and URS. Patient information was collected as part of routine visits and telehealth consultations. Results ACCROS-I: There was a statistically significant difference in the rate of clinical recovery (P<0.05) in Δ%DSS (M -18.8±SEM 7.9%) and Δ%VAS (-8.6±5.1%), such that the CPM group reported fewer symptoms than PLB. The proportion of patients who reported sensory deficits and URS at day 7 was significantly lower (P<0.05) in CPM vs. PLB for ageusia (1.7% vs. 15.0%), cough (16.4% vs. 35.0%) and nasal congestion (8.1%vs.20%). None of the patients required hospitalization. ACCROS-II: There was a statistically significant reduction (P<0.05) in total days reporting URS for general symptoms of COVID-19 in CPM+SoC (5.1 ± 0.1) compared to SoC (11.0 ± 0.2). CPM+SoC users also showed fewer days with cough, anosmia, and ageusia. Persistent anosmia (over 29 days) was found in 3% of the patients on SoC, whereas no persistent anosmia was reported in the CPM+SoC cohort (X2 = 10.18; P<0.001). Conclusion: The result of this two-part study supports the conclusion that intranasal CPM is an antiviral agent that can be administered intranasally to treat COVID-19-induced symptoms effectively. Intranasal CPM accelerates clinical recovery and reduces URS in patients with mild to moderate COVID-19. This study's important implications include individuals returning to daily life faster, reducing community and individual economic burden, and decreasing healthcare utilization. Trial registration: ClinicalTrials.gov.; ID: NCT05449405 ACCROS-I retrospectively registered on 7/13/2022, NCT05520944 ACCROS-R retrospectively registered on 08/27/2022.

Antidepressant augmentation upon intranasal Galanin and Neuropeptide Y agonists enhanced ventral hippocampal proliferative and neurotrophic actions (preprint)

Background: and Purpose: Dysregulation of adult hippocampal neurogenesis is linked to major depressive disorder (MDD), with more than 300 million people diagnosed and worsened by the COVID-19 pandemic. Accumulating evidence for Neuropeptide Y (NPY) and galanin (GAL) interaction was shown in various limbic system regions at molecular-,cellular- and behavioral-specific levels. The purpose of the current work was to evaluate the proliferating role of GALR2 and Y1R agonists interaction upon intranasal infusion in the ventral hippocampus. Experimental approach: We studied their hippocampal proliferating actions using the proliferating cell nuclear antigen (PCNA) and the expression of of the brain-derived neurothrophic factor (BDNF). Moreover, we studied the formation of Y1R-GALR2 heteroreceptor complexes and analyzed morphological changes on hippocampal neuronal cells. Finally, the functional outcome of the NPY and GAL interaction on the ventral hippocampus was evaluated in the forced swimming test. Key Results: We demonstrated that the intranasal infusion of GALR2 and the Y1R agonists promotes cell proliferation in the DG of the ventral hippocampus and the induction of the neurotrophic factor BDNF. These effects were mediated by the increased formation of Y1R-GALR2 heteroreceptor complexes, which may mediate the neurites outgrowth observed on neuronal hippocampal cells. Importantly, BDNF action was found necessary for the antidepressant-like effects after GALR2 and the Y1R agonists intranasal administration. Conclusions & Implications: Our data may suggest the translational development of new heterobivalent agonist pharmacophores acting on Y1R–GALR2 heterocomplexes in the ventral hippocampus for the novel therapy of mayor depression disorder or depressive-affecting diseases.

Cannabis Use and Emotional Intelligence in Adolescents during COVID-19 Confinement: A Social Network Analysis Approach

Confinement by COVID-19 had negative consequences on adolescent mental health, including increased cannabis use. Cannabis is related to variables that influence health and well-being. Emotional Intelligence is associated with adaptive coping styles, peer relationships, and social–emotional competencies. In adolescence, peer selection plays a unique role in the initiation of substance use. However, there are no studies during a confinement stage that analyse the relationships between networks, Emotional Intelligence, and cannabis use. The aim of this paper is to describe and analyse the consumption and friendship networks of an adolescent classroom and their relationship with Emotional Intelligence, cannabis use, and gender during COVID-19 confinement. Participants completed different questionnaires for Emotional Intelligence, cannabis use, and the consumption and friendship network. The sample consisted of 21 students from 10th grade, of which 47.6% were consumers. The friendship network correlates with the consumption network, and significant associations between emotional repair and being a cannabis user. The regression model points to the friendship network as a significant variable in predicting the classroom use network. This study highlights the role of the Social Network Analysis in predicting consumption networks during a COVID-19 confinement stage and serves as a tool for cannabis use prevention interventions in a specific population.

Prevalence and Prognostic Value of Myocardial Injury in the Initial Presentation of SARS-CoV-2 Infection among Older Adults (preprint)

Myocardial involvement during SARS-CoV-2 infection has been reported in many prior publications. Data about this condition in older adults is scarce especially its role in clinical prognosis. We aim to study the prevalence and the clinical implications of acute myocardial injury (MIN) during SARS-CoV-2 infection, particularly in older patients.MethodsLongitudinal observational study where all consecutive adult patients admitted to a COVID-19 unit between March to April 2020 were included. Those patients aged ≥65 were considered as older patients. MIN was defined as at least 1 high-sensitive troponin (hs-TnT) concentration above the 99th percentile upper reference limit with different sex-cutoff.ResultsAmong the 634 patients admitted during the period of observation 365(58%) had evidence of MIN (hs-TnT>14 pg/mL), and among those 224(61%) were older adults. Individuals with acute MIN were more prone to be older, had more comorbidities, more functional decline at admission, and higher inflammatory parameters. Among older adults, MIN was associated with longer time to recovery compared to those without MIN [13 days(IQR 6-21) vs 9 days(IQR 5-17);p<0.001 repectively. In-hospital mortality was significantly higher in older adults with MIN at admission vs those without MIN [71(31%) vs 11(12%);p<0.001]. In a logistic regression model adjusting by age, sex, severity and Charlson comorbidity index the OR for in-hospital mortality was 2.1 (95% CI:1.02-4.42;p=0.043) among those older adults with MIN at presentation.ConclusionMIN is frequent in individuals with SARS-CoV-2 infection, especially in older adults and in patients with pre-existing comorbidities and with higher inflammatory levels. Older adults with acute myocardial injury had greater time to clinical recovery, more severe presentation of the disease and higher odds of in-hospital mortality.  

Prevention of severe COVID-19 in the elderly by early high-titer plasma (preprint)

BackgroundTherapies to interrupt progression of early COVID-19 remain elusive. Among them, convalescent plasma in hospitalized patients was unsuccessful, perhaps because antibody should be administered earlier. We advanced plasma infusions to the first 72 hours of symptoms to arrest COVID-19 progression. MethodsA randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against SARS-CoV2 in elderly subjects within 72 hours of mild COVID-19 symptoms. The primary endpoint was severe respiratory disease defined as a respiratory rate [≥]30 and/or an O2 sat<93% in room air. The study was interrupted at 76% of its projected sample size, because cases in the region decreased considerably and steady enrollment of study subjects became virtually impossible. Results160 patients underwent randomization. In the intention-to-treat analysis (ITT), 13/80(16.2%) patients receiving plasma vs. 25/80(31.2%) receiving placebo experienced severe respiratory disease [RR(95%CI)= 0.52(0.29,0.94); p=0.026)] with an RRR=48%. A modified ITT analysis, excluding six subjects who experienced the primary endpoint before infusion, showed a larger effect size [RR(95%CI) = 0.40(0.20, 0.81), p=0.007]. High- and low-titer donor analyses, based on a median IgG titer=1:3,200, evidenced a dose-dependent response with an RRR=73.3% for recipients of high-titer plasma (p=0.016) and a number needed to treat (NNT)=4.4. All secondary endpoints exhibited trends towards protection. No solicited adverse events were observed. ConclusionsEarly administration of high-titer convalescent plasma against SARS-CoV2 to mildly ill infected seniors reduced COVID-19 progression. This safe, inexpensive, outpatient intervention facilitates access to treatment from industrialized to LMIC, can decompress demands on hospitals, and may contribute to save lives. Funded by The Bill & Melinda Gates Foundation and The Fundacion INFANT Pandemic Fund. Registered in the Direccion de Sangre y Medicina Transfusional del Ministerio de Salud (PAEPCC19), Plataforma PRIISA (1421), and clinicaltrials.gov (NCT04479163). All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the submitted work; RL, GPM, DW and FPP are investigators in a phase 3 SARS CoV2 trial from Pfizer; no other relationships or activities that could appear to have influenced the submitted work.

Modeling the frequency and number of persons to test to detect and control COVID-19 outbreaks in congregate settings (preprint)

BackgroundCongregate settings are at risk for coronavirus disease 2019 (COVID-19) outbreaks. Diagnostic testing can be used as a tool in these settings to identify outbreaks and to control transmission. MethodsWe used transmission modeling to estimate the minimum number of persons to test and the optimal frequency to detect small outbreaks of COVID-19 in a congregate facility. We also estimated the frequency of testing needed to interrupt transmission within a facility. ResultsThe number of people to test and frequency of testing needed depended on turnaround time, facility size, and test characteristics. Parameters are calculated for a variety of scenarios. In a facility of 100 people, 26 randomly selected individuals would need to be tested at least every 6 days to identify a true underlying prevalence of at least 5%, with test sensitivity of 85%, and greater than 95% outbreak detection sensitivity. Disease transmission could be interrupted with universal, facility-wide testing with rapid turnaround every three days. ConclusionsTesting a subset of individuals in congregate settings can improve early detection of small outbreaks of COVID-19. Frequent universal diagnostic testing can be used to interrupt transmission within a facility, but its efficacy is reliant on rapid turnaround of results for isolation of infected individuals.

Low Zinc Levels at Clinical Admission Associates with Poor Outcomes in COVID-19 (preprint)

Background: Biomarkers to predict Coronavirus disease-19 (COVID-19) outcome early at infection are urgently needed to improve prognosis and treatment. Zinc balances immune responses and also has a proven direct antiviral action against some viruses. Importantly, zinc deficiency (ZD) is a common condition in elderly and individuals with chronic diseases, two groups with more severe COVID-19 outcomes. We hypothesize that serum zinc content (SZC) influences COVID-19 disease progression and thus might represent a useful biomarker.Methods: We run a retrospective observational study with 249 COVID-19 patients admitted in Hospital del Mar. We have studied COVID-19 severity and progression attending to SZC at admission. In parallel we have studied SARS-CoV2 replication in the Vero E6 cell line modifying zinc concentrations.Findings: Our study demonstrates a correlation between serum zinc levels and COVID-19 outcome. Serum zinc levels lower than 50 µg/dl at admission correlated with worse clinical presentation, longer time to reach stability and higher mortality. Our in vitro results indicate that low zinc levels favor viral expansion in SARS-CoV2 infected cells.Interpretation: SZC is a novel biomarker to predict COVID-19 outcome. We encourage performing randomized clinical trials to study zinc supplementation as potential prophylaxis and treatment with people at risk of zinc deficiency.Funding: This work was supported by the Spanish Ministry of Science and Innovation through grants PID2019-106755RB-I00/AEI/10.13039/501100011033 to RV and PID2019-106959RB-I00/AEI /10.13039/501100011033 to JD, an institutional “Maria de Maeztu” Programme for Units of Excellence in R&D (CEX2018-000792-M) to RV and JD and by the 2017 SGR 909 grant from the Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement of the Generalitat de Catalunya to JD. RGF received support and funding from Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES) [Grant number CB16/10/00245], FEDER funds and the FIS Project from Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación [Grant number (PI19/00019)]Declaration of Interests: The authors declare that no competing interests exist.Ethics Approval Statement: The Institutional Ethics Committee of Hospital del Mar of Barcelona approved the study and due to the nature of the retrospective data review, and waived the need for informed consent from individual patients (CEIm 2020/9352).

Low zinc levels at clinical admission associates with poor outcomes in COVID-19 (preprint)

Background: Biomarkers to predict Coronavirus disease-19 (COVID-19) outcome early at infection are urgently needed to improve prognosis and treatment. Zinc balances immune responses and also has a proven direct antiviral action against some viruses. Importantly, zinc deficiency (ZD) is a common condition in elderly and individuals with chronic diseases, two groups with more severe COVID-19 outcomes. We hypothesize that serum zinc content (SZC) influences COVID-19 disease progression and thus might represent a useful biomarker. Methods: We run a retrospective observational study with 249 COVID-19 patients admitted in Hospital del Mar. We have studied COVID-19 severity and progression attending to SZC at admission. In parallel we have studied SARS-CoV2 replication in the Vero E6 cell line modifying zinc concentrations. Findings: Our study demonstrates a correlation between serum zinc levels and COVID-19 outcome. Serum zinc levels lower than 50 mcgg/dl at admission correlated with worse clinical presentation, longer time to reach stability and higher mortality. Our in vitro results indicate that low zinc levels favor viral expansion in SARS-CoV2 infected cells. Interpretation: SZC is a novel biomarker to predict COVID-19 outcome. We encourage performing randomized clinical trials to study zinc supplementation as potential prophylaxis and treatment with people at risk of zinc deficiency.