Gastrointestinal manifestations of long-term effects after COVID-19 infection in patients with dialysis or kidney transplantation: An observational cohort study.

BACKGROUND: Prolonged symptoms after corona virus disease 2019 (Long-COVID) in dialysis-dependent patients and kidney transplant (KT) recipients are important as a possible risk factor for organ dysfunctions, especially gastrointestinal (GI) problems, during immunosuppressive therapy. AIM: To identify the characteristics of GI manifestations of Long-COVID in patients with dialysis-dependent or KT status. METHODS: This observational, prospective study included patients with COVID-19 infection, confirmed by reverse transcription polymerase chain reaction, with the onset of symptoms between 1 January 2022 and 31 July 2022 which was explored at 3 mo after the onset, either through the out-patient follow-up or by telephone interviews. RESULTS: The 645 eligible participants consisted of 588 cases with hemodialysis (HD), 38 patients with peritoneal dialysis (PD), and 19 KT recipients who were hospitalized with COVID-19 infection during the observation. Of these, 577 (89.5%) cases agreed to the interviews, while 64 (10.9%) patients with HD and 4 (10.5%) cases of PD were excluded. The mean age was 52 ± 11 years with 52% women. The median dialysis duration was 7 ± 3 and 5 ± 1 years for HD and PD groups, respectively, and the median time post-transplantation was 6 ± 2 years. Long-COVID was identified in 293/524 (56%) and 21/34 (62%) in HD and PD, respectively, and 7/19 (37%) KT recipients. Fatigue was the most prevalent (96%) of the non-GI tract symptoms, whereas anorexia (90.9%), loss of taste (64.4%), and abdominal pain (62.5%) were the first three common GI manifestations of Long-COVID. Notably, there were 6 cases of mesenteric panniculitis from 19 patients with GI symptoms in the KT group. CONCLUSION: Different from patients with non-chronic kidney disease, there was a high prevalence of GI manifestations of Long-COVID in dialysis-dependent patients and KT recipients. An appropriate long-term follow-up in these vulnerable populations after COVID-19 infection is possibly necessary.

Pharmacometrics of high-dose ivermectin in early COVID-19 from an open label, randomized, controlled adaptive platform trial (PLATCOV).

Background: There is no generally accepted methodology for in vivo assessment of antiviral activity in SARS-CoV-2 infections. Ivermectin has been recommended widely as a treatment of COVID-19, but whether it has clinically significant antiviral activity in vivo is uncertain. Methods: In a multicentre open label, randomized, controlled adaptive platform trial, adult patients with early symptomatic COVID-19 were randomized to one of six treatment arms including high-dose oral ivermectin (600 µg/kg daily for 7 days), the monoclonal antibodies casirivimab and imdevimab (600 mg/600 mg), and no study drug. The primary outcome was the comparison of viral clearance rates in the modified intention-to-treat population. This was derived from daily log10 viral densities in standardized duplicate oropharyngeal swab eluates. This ongoing trial is registered at https://clinicaltrials.gov/ (NCT05041907). Results: Randomization to the ivermectin arm was stopped after enrolling 205 patients into all arms, as the prespecified futility threshold was reached. Following ivermectin, the mean estimated rate of SARS-CoV-2 viral clearance was 9.1% slower (95% confidence interval [CI] -27.2% to +11.8%; n=45) than in the no drug arm (n=41), whereas in a preliminary analysis of the casirivimab/imdevimab arm it was 52.3% faster (95% CI +7.0% to +115.1%; n=10 (Delta variant) vs. n=41). Conclusions: High-dose ivermectin did not have measurable antiviral activity in early symptomatic COVID-19. Pharmacometric evaluation of viral clearance rate from frequent serial oropharyngeal qPCR viral density estimates is a highly efficient and well-tolerated method of assessing SARS-CoV-2 antiviral therapeutics in vitro. Funding: 'Finding treatments for COVID-19: A phase 2 multi-centre adaptive platform trial to assess antiviral pharmacodynamics in early symptomatic COVID-19 (PLAT-COV)' is supported by the Wellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator. Clinical trial number: NCT05041907.

Safety and immunogenicity of an inactivated recombinant Newcastle disease virus vaccine expressing SARS-CoV-2 spike: Interim results of a randomised, placebo-controlled, phase 1 trial.

Background: Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and middle-income countries is needed. NDV-HXP-S is an inactivated egg-based recombinant Newcastle disease virus vaccine expressing the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It's being developed by public sector manufacturers in Thailand, Vietnam, and Brazil; herein are initial results from Thailand. Methods: This phase 1 stage of a randomised, dose-escalation, observer-blind, placebo-controlled, phase 1/2 trial was conducted at the Vaccine Trial Centre, Mahidol University (Bangkok). Healthy males and non-pregnant females, aged 18-59 years and negative for SARS-CoV-2 antibodies, were eligible. Participants were randomised to receive one of six treatments by intramuscular injection twice, 28 days apart: 1 µg, 1 µg+CpG1018 (a toll-like receptor 9 agonist), 3 µg, 3 µg+CpG1018, 10 µg, or placebo. Participants and personnel assessing outcomes were masked to treatment. The primary outcomes were solicited and spontaneously reported adverse events (AEs) during 7 and 28 days after each vaccination, respectively. Secondary outcomes were immunogenicity measures (anti-S IgG and pseudotyped virus neutralisation). An interim analysis assessed safety at day 57 in treatment-exposed individuals and immunogenicity through day 43 per protocol. ClinicalTrials.gov (NCT04764422). Findings: Between March 20 and April 23, 2021, 377 individuals were screened and 210 were enroled (35 per group); all received dose one; five missed dose two. The most common solicited AEs among vaccinees, all predominantly mild, were injection site pain (<63%), fatigue (<35%), headache (<32%), and myalgia (<32%). The proportion reporting a vaccine-related AE ranged from 5·7% to 17·1% among vaccine groups and was 2·9% in controls; there was no vaccine-related serious adverse event. The 10 µg formulation's immunogenicity ranked best, followed by 3 µg+CpG1018, 3 µg, 1 µg+CpG1018, and 1 µg formulations. On day 43, the geometric mean concentrations of 50% neutralising antibody ranged from 122·23 international units per mL (IU/mL; 1 µg, 95% confidence interval (CI) 86·40-172·91) to 474·35 IU/mL (10 µg, 95% CI 320·90-701·19), with 93·9% to 100% of vaccine groups attaining a ≥ 4-fold increase over baseline. Interpretation: NDV-HXP-S had an acceptable safety profile and potent immunogenicity. The 3 µg and 3 µg+CpG1018 formulations advanced to phase 2. Funding: National Vaccine Institute (Thailand), National Research Council (Thailand), Bill & Melinda Gates Foundation, National Institutes of Health (USA).

High Mobility Group Box 1 and Interleukin 6 at Intensive Care Unit Admission as Biomarkers in Critically Ill COVID-19 Patients.

Exuberant inflammation manifesting as a "cytokine storm" has been suggested as a central feature in the pathogenesis of severe coronavirus disease 2019 (COVID-19). This study investigated two prognostic biomarkers, the high mobility group box 1 (HMGB1) and interleukin-6 (IL-6), in patients with severe COVID-19 at the time of admission in the intensive care unit (ICU). Of 60 ICU patients with COVID-19 enrolled and analyzed in this prospective cohort study, 48 patients (80%) were alive at ICU discharge. HMGB1 and IL-6 plasma levels at ICU admission were elevated compared with a healthy control, both in ICU nonsurvivors and ICU survivors. HMGB1 and IL-6 plasma levels were higher in patients with a higher Sequential Organ Failure Assessment (SOFA) score (> 10), and the presence of septic shock or acute kidney injury. HMGB1 and IL-6 plasma levels were also higher in patients with a poor oxygenation status (PaO2/FiO2 < 150 mm Hg) and a longer duration of ventilation (> 7 days). Plasma HMGB1 and IL-6 levels at ICU admission also correlated with other prognostic markers, including the maximum neutrophil/lymphocyte ratio, D-dimer levels, and C-reactive protein levels. Plasma HMGB1 and IL-6 levels at ICU admission predicted ICU mortality with comparable accuracy to the SOFA score and the COVID-GRAM risk score. Higher HMGB1 and IL-6 were not independently associated with ICU mortality after adjustment for age, gender, and comorbidities in multivariate analysis models. In conclusion, plasma HMGB1 and IL6 at ICU admission may serve as prognostic biomarkers in critically ill COVID-19 patients.

Social restriction versus herd immunity policies in the early phase of the SARS-CoV-2 pandemic: A mathematical modelling study.

BACKGROUND: Two main strategies to cope with the coronavirus disease 2019 (COVID-19) pandemic-lockdown (social restriction) and non-lockdown (herd immunity plan)-have been implemented in several countries. OBJECTIVE: This study aims to statistically compare the outcomes of the two strategies, represented by data from Thailand and Sweden, respectively. METHODS: Data for COVID-19 pandemic control from Thailand, representing social restriction, versus data from Sweden, representing the herd immunity plan, collected from January 13 to May 31, 2020, were analyzed by using the SIR (susceptible, infectious, recovered) model. RESULTS: The SIR model analysis demonstrated a beneficial effect of each model on the attenuation of the mortality rate, with lower mortality in social restriction and shorter overall pandemic duration in the herd immunity plan. However, the herd immunity plan demonstrated a higher mortality rate than social restriction (46.9% versus 1.9%) despite the later entry of the virus in Sweden. When the SIR model was used for predicting the COVID-19 status, Sweden was shown to likely end its COVID-19 epidemic earlier than Thailand (268 vs. 368 days). With the nonlinear estimation, at least one log difference between total confirmed cases versus active cases could be used as an indicator for relaxation of the lockdown policy in Thailand. CONCLUSIONS: Both the social restriction and herd immunity plans are beneficial for COVID-19 pandemic control in terms of the amelioration of pandemic mortality. The cumulative number of total recovered cases might be a potential parameter that could be used for determining the policy direction for COVID-19 control.