Viral and symptom rebound following anti-SARS-CoV-2 monoclonal antibody therapy in a randomized placebo-controlled trial.

We explored viral and symptom rebound after COVID-19 amubarvimab/romlusevimab monoclonal antibody therapy vs placebo in the randomized ACTIV-2/A5401 trial. Participants underwent nasal SARS-CoV-2 PCR at study days 3, 7, 14, and 28. Viral rebound was defined as RNA ≥3 and ≥0.5 log10 copies/mL increase from day 3 or 7, and symptom rebound as hospitalization or any moderate/severe symptom for ≥2 days after initial symptom improvement. There was no difference in viral rebound (∼5%/arm) (analysis population n=713) or symptom rebound among participants who initially improved (hazard ratio 0.95 (95% CI 0.52, 1.75, analysis population) n=574); <1% had both viral/symptom rebound.

Brain 18F-FDG PET imaging in outpatients with post-COVID-19 conditions: findings and associations with clinical characteristics.

BACKGROUND: Brain 18F-FDG PET imaging has the potential to provide an objective assessment of brain involvement in post-COVID-19 conditions but previous studies of heterogeneous patient series yield inconsistent results. The current study aimed to investigate brain 18F-FDG PET findings in a homogeneous series of outpatients with post-COVID-19 conditions and to identify associations with clinical patient characteristics. METHODS: We retrospectively included 28 consecutive outpatients who presented with post-COVID-19 conditions between September 2020 and May 2022 and who satisfied the WHO definition, and had a brain 18F-FDG PET for suspected brain involvement but had not been hospitalized for COVID-19. A voxel-based group comparison with 28 age- and sex-matched healthy controls was performed (p-voxel at 0.005 uncorrected, p-cluster at 0.05 FWE corrected) and identified clusters were correlated with clinical characteristics. RESULTS: Outpatients with post-COVID-19 conditions exhibited diffuse hypometabolism predominantly involving right frontal and temporal lobes including the orbito-frontal cortex and internal temporal areas. Metabolism in these clusters was inversely correlated with the number of symptoms during the initial infection (r = - 0.44, p = 0.02) and with the duration of symptoms (r = - 0.39, p = 0.04). Asthenia and cardiovascular, digestive, and neurological disorders during the acute phase and asthenia and language disorders during the chronic phase (p ≤ 0.04) were associated with these hypometabolic clusters. CONCLUSION: Outpatients with post-COVID-19 conditions exhibited extensive hypometabolic right fronto-temporal clusters. Patients with more numerous symptoms during the initial phase and with a longer duration of symptoms were at higher risk of persistent brain involvement.

Treatment Options for Patients With Mild-to-Moderate Coronavirus Disease 2019 in Korea.

The coronavirus disease 2019 (COVID-19) continues to threaten public health in Korea although several surges have passed in the past 3 years since 2019. Although patients with mild-to-moderate COVID-19 can usually recover at home, antiviral therapy to prevent disease progression and hospitalization is beneficial for those at high risk of progressing to severe COVID-19. The purpose of this article was to review how antivirals have been rolled out for the treatment of COVID-19 and how domestic and international guidelines for their use have evolved. Several evidence-based treatment guidelines have been developed in Korea, including those derived from domestic studies. Although many different antiviral agents were nominated as promising therapeutics at the onset of the pandemic, most failed to show efficacy in clinical trials. Currently, three types of antiviral agents-nirmatrelvir-ritonavir, molnupiravir, and remdesivir-are available in Korea to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Each antiviral has its advantages and disadvantages. For most individuals, nirmatrelvir/ritonavir is preferred because of its high efficacy and convenience of administration. When serious drug interactions occur or are expected with nirmatrelvir/ritonavir administration, 3 days of remdesivir treatment is shown to be a reasonable alternative. Molnupiravir may be prescribed with caution only if no other therapeutic options are available or acceptable.

[Mild SARS-CoV-2 infection in vulnerable patients: implementation of a clinical pathway for early treatment]. / Infección leve por SARS-CoV-2 en pacientes vulnerables: implantación de una vía clínica de tratamiento precoz.

INTRODUCTION: The objective of this report is to describe the clinical pathway for early treatment of patients with acute SARS-CoV-2 infection and to evaluate the first results of its implementation. METHODS: This is a descriptive and retrospective study of the implementation of a clinical pathway of treatment in outpatients (January 1 to June 30 2022). Clinical pathway: detection and referral systems from Primary Care, Emergency services, hospital specialities and an automated detection system; clinical evaluation and treatment administration in the COVID-19 day-hospital and subsequent clinical follow-up. Explanatory variables: demographics, comorbidity, vaccination status, referral pathways and treatment administration. OUTCOME VARIABLES: hospitalization and death with 30 days, grade 2-3 toxicity related to treatment. RESULTS: Treatment was administered to 262 patients (53,4% women, median age 60 years). The treatment indication criteria were immunosupression (68,3%), and the combination of age, vaccination status and comorbidity in the rest47,3% of the patients s received remdesivir, 35,9% nirmatrelvir/ritonavir, 13,4% sotrovimab and 2,4% combined treatment with a median of 4 days after symptom onset. Hospital admission was required for 6,1% of the patients, 3,8% related to progression COVID-19. No patient died. Toxicity grade 2-3 toxicity was reported in 18,7%, 89,8% dysgeusia and metallic tasted related nirmatrelvir/ritonavir. Seven patients discontinued treatment due to toxicity. CONCLUSION: The creation and implementation of a clinical pathway for non-hospitalized patients with SARS-CoV-2 infection is effective and it allows early accessibility and equity of currently available treatments.

Efficacy and safety of ivermectin for treatment of non-hospitalized COVID-19 patients: A systematic review and meta-analysis of 12 randomized controlled trials with 7,035 participants.

INTRODUCTION: We systematically assessed benefits and harms of the use of ivermectin in non-hospitalized patients with early COVID-19. METHODS: Five databases were searched until October 17, 2023, for randomized controlled trials (RCTs) in adult patients with COVID-19 treated with ivermectin against standard of care (SoC), placebo, or active drug. Primary outcomes were hospitalization, all-cause mortality, and adverse events (AEs). Secondary outcomes included mechanical ventilation (MV), clinical improvement, clinical worsening, viral clearance, and severe adverse events (SAEs). Random effects meta-analyses were performed, with quality of evidence (QoE) evaluated using GRADE methods. Pre-specified subgroup analyses (ivermectin dose, control type, risk of bias, follow-up, and country income) and trial sequential analysis (TSA) were performed. RESULTS: Twelve RCTs (n = 7,035) were included. The controls were placebo in nine RCTs, SoC in two RCTs, and placebo or active drug in one RCT. Ivermectin did not reduce hospitalization (relative risk [RR], 0.81, 95% confidence interval [95% CI] 0.64-1.03; 8 RCTs, low QoE), all-cause mortality (RR 0.98, 95% CI 0.73-1.33; 9 RCTs, low QoE), or AEs (RR 0.89, 95% CI 0.75-1.07; 9 RCTs, very low QoE) vs. controls. Ivermectin did not reduce MV, clinical worsening, or SAEs and did not increase clinical improvement and viral clearance vs. controls (very low QoE for secondary outcomes). Subgroup analyses were mostly consistent with main analyses, and TSA-adjusted risk for hospitalization was similar to main analysis. CONCLUSIONS: In non-hospitalized COVID-19 patients, ivermectin did not have effect on clinical, non-clinical or safety outcomes versus controls. Ivermectin should not be recommended as treatment in non-hospitalized COVID-19 patients.

Hospitalization Endpoint in Clinical Trials of Outpatient Settings: using Anti-SARS-COV-2 Therapy as an Example.

Purpose: In response to the COVID-19 pandemic, the World Health Organization (WHO) developed a set of outcome measures for trials primarily aimed at hospitalised patients. However, a gap exists in defining outcome standards for non-hospitalised patients. Therefore, this study aims to discuss hospitalisation as a primary outcome in outpatient trials and its potential pitfalls, specifically focusing on trials related to anti-SARS-COV-2 therapy. Methods: In this narrative review, researchers thoroughly searched MEDLINE and ClinicalTrials.gov from January 2020 to December 2022, targeting Phase III randomized controlled trials involving outpatients with mild-to-moderate COVID-19. The trials were specifically related to anti-SARS-COV-2 monoclonal antibodies or antiviral agents. The study collected essential data, including the type of intervention, comparator, primary objective, primary endpoint, and the use of estimands in the trial. Results: The search identified 12 trials that evaluated the efficacy of anti-SARS COV-2 therapies in a predefined population. Three studies used hospitalisation and death as primary endpoints in high-risk patients receiving monoclonal antibodies. Nine studies assessed the efficacy of several antiviral agents: four trials used hospitalisation and death as the main endpoints, while others used different measures such as virologic measures using the Reverse Transcription-Polymerase Chain Reaction test (RT-PCR), the eight-point WHO ordinal scale, symptom alleviation by Day 7 and time to clinical response. Conclusion: Choosing hospitalization as an endpoint may provide meaningful data such as the cost-effectiveness ratio of a drug. However, different hospital utilisation patterns and investigator decisions could bias clinical outcomes if no specific criteria are considered. Therefore, investigators should have clear criteria for determining variables that influence this measure.

Growth Differentiation Factor-15 Is Considered a Predictive Biomarker of Long COVID in Non-hospitalized Patients.

Mitochondrial dysfunction is associated with various diseases. Mitochondria plays a regulatory role during infection. The association between mitokines and subsequent COVID progression has not been previously studied. The retrospective cohort study aimed to investigate the potential of serum mitokines as long COVID biomarkers in non-hospitalized patients. Patients with confirmed SARS-CoV-2 infection and blood test reports between January 2021 and April 2023 were included. Patients were categorized into two groups, the recovered and long COVID groups, based on fatigue, decline in focus, and pain. Serum levels of growth differentiation factor 15 (GDF-15) and fibroblast growth factor-21 (FGF-21), which are affected by mitochondrial function, along with inflammatory and vascular endothelium markers, were measured using enzyme-linked immunosorbent assays (ELISA). A receiver operating characteristic curve was used to screen the biomarkers. The threshold value of GDF-15 in the acute phase was 965 pg/mL (sensitivity: 71.4%, specificity: 83.3%), indicating that GDF-15 may be associated with the presence of symptoms three months post onset. No association with inflammatory markers and vascular structures was observed. Therefore, elevated GDF-15 levels in the acute phase may act as a predictive biomarker of long COVID.

Long-COVID-19 Impact in non-hospitalized patients: Sleep and quality of life 24 months after SARS-CoV-2 infection.

Background and Aims: Sleep disruption and reduced quality of life are common long coronavirus disease (COVID) manifestations, affecting survivors irrespective of initial COVID-19 severity. Limited research investigates symptoms beyond 24 months post-infection. We aimed to address this gap by longitudinally studying sleep patterns and overall quality of life in non-hospitalized adults, 24 months after severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Methods: This prospective observational study involved the enrolment of 337 adult non-hospitalized patients in a consecutive fashion. Individuals with past COVID-19 (from 15 April 2020 to 30 June 2021) were examined at two Government hospitals and completed a telephone interview between 1 May 2023 and 30 June 2023, located in Jharkhand, India. Participants were queried about their sleep patterns and quality of life, utilizing the DSM5 LEVEL 2 and EQ-ED-5L tool, respectively. Results: Among 337 non-hospitalized participants, 212 completed the survey. Within this group (59.4% men, mean age 38), 36 (17.0%) experienced sleep impairment. All five dimensions of quality of life (QoL) were adversely affected in long COVID patients. Advanced age, high income, residing in rural or semi-urban areas, and having comorbidities were associated with a higher likelihood of decreased quality of life across various domains. Conversely, participants who were married, employed in healthcare or government positions, and vaccinated exhibited a reduced likelihood of experiencing lower quality of life. Conclusion: Long COVID-19 affects sleep and quality of life, with various demographic and clinical factors influencing outcomes. This study provides insights into the extended consequences of long COVID-19 and aids healthcare systems in addressing the challenges posed by this condition.

Mild SARS-CoV-2 infection in vulnerable patients: implementation of a clinical pathway for early treatment.

INTRODUCTION: The objective of this report is to describe the clinical pathway for early treatment of patients with acute SARS-CoV-2 infection and to evaluate the first results of its implementation. METHODS: This is a descriptive and retrospective study of the implementation of a clinical pathway of treatment in outpatients (January 1 to June 30 2022). Clinical pathway: detection and referral systems from Primary Care, Emergency services, hospital specialities and an automated detection system; clinical evaluation and treatment administration in the COVID-19 day-hospital and subsequent clinical follow-up. Explanatory variables: demographics, comorbidity, vaccination status, referral pathways and treatment administration. OUTCOME VARIABLES: hospitalization and death with 30 days, grade 2-3 toxicity related to treatment. RESULTS: Treatment was administered to 262 patients (53,4% women, median age 60 years). The treatment indication criteria were immunosupression (68,3%), and the combination of age, vaccination status and comorbidity in the rest 47,3% of the patients s received remdesivir, 35,9% nirmatrelvir/ritonavir, 13,4% sotrovimab and 2,4% combined treatment with a median of 4 days after symptom onset. Hospital admission was required for 6,1% of the patients, 3,8% related to progression COVID-19. No patient died. Toxicity grade 2-3 toxicity was reported in 18,7%, 89,8% dysgeusia and metallic tasted related nirmatrelvir/ritonavir. Seven patients discontinued treatment due to toxicity. CONCLUSION: The creation and implementation of a clinical pathway for non-hospitalized patients with SARS-CoV-2 infection is effective and it allows early accessibility and equity of currently available treatments.

Self-Reported Persistent Symptoms at 18 Months and Above Among COVID-19 Non-hospitalized Patients: A Prospective Cohort Study.

INTRODUCTION: Since the beginning of the pandemic in early 2020, there have been numerous reports of symptoms that have lingered due to COVID-19. However, there is a lack of data concerning these persistent symptoms in non-hospitalized patients. This study sought to examine the prevalence of persistent symptoms at 18 months and beyond following the diagnosis of COVID-19 non-hospitalized patients. METHODS: A prospective cohort study comprised 212 non-hospitalized adult patients consecutively assessed from data available at tertiary care institutions through telephone interviews. During the interview, participants were routinely questioned about whether they were still experiencing any post-infection symptoms at the time of the study. RESULTS: Total 212 took part in the 18-month or longer follow-up survey. The most commonly reported symptoms during the acute phase were fever (n=149, 70.3%), weakness (n=118, 55.7%), and sore throat (n=100, 47.2%). At the 18-month and above follow-up, 167 patients (78.7%) reported at least one symptom continuing. The most common symptom at this time point was fatigue (n=109, 51.4%), followed by joint pain (n=57, 26.8%), and exertional dyspnea (24.5%). The possibility of symptoms returning after an 18-month follow-up and beyond was significantly lower in patients who had taken the COVID-19 vaccine (OR=0.29; 95% CI: 0.112-0.749; p=0.011) and those did not infect a second time (OR=0.232; 95% CI: 0.057-0.93; p=0.04). CONCLUSION: The present study reveals that clinical complications persist even at 18 months and beyond during follow-up, with a prevalence similar to earlier follow-up periods, regardless of the severity of the initial COVID-19 infection.

A pilot phase 2a, randomized, double-blind, placebo-controlled study to explore the antiviral activity, clinical outcomes, safety, and tolerability of rilematovir at two dose levels in non-hospitalized adults with respiratory syncytial virus infection.

OBJECTIVES: To assess the antiviral effect, clinical outcomes, and safety of the respiratory syncytial virus (RSV) fusion inhibitor rilematovir in non-hospitalized RSV-infected adults. METHODS: This phase 2a, double-blind, multicentre study randomly assigned RSV-positive adult outpatients ≤5 days from symptom onset 1:1:1 to receive rilematovir 500 mg, 80 mg, or placebo once-daily for 7 days. Antiviral effect was assessed by RSV RNA viral load (VL), measured by quantitative RT-PCR, and Kaplan-Meier (KM) estimates of time to undetectable VL. Clinical course was assessed by KM estimates of median time to resolution of key RSV symptoms assessed through patient-reported outcomes. RESULTS: RSV-positive patients (n = 72) were randomly assigned; 66 had confirmed RSV infection and received rilematovir 500 mg (n = 23), 80 mg (n = 21) or placebo (n = 22). Differences versus placebo in mean RSV RNA VL area under the curve (90% CI) through days 3, 5 and 8, respectively, were 0.09 (-0.837; 1.011), -0.10 (-2.171; 1.963), and -1.03 (-4.746; 2.682) log10 copies.day/mL for rilematovir 500 mg, and 1.25 (0.291; 2.204), 2.53 (0.430; 4.634), and 3.85 (0.097; 7.599) log10 copies.day/mL for rilematovir 80 mg. KM estimates of median (90% CI) time-to-first confirmed undetectable VL were 5.9 (3.85; 6.90), 8.0 (6.86; 12.80) and 7.0 (6.62; 10.88) days and 5.7 (2.93; 7.01), 8.1 (6.74; 12.80) and 7.9 (6.62; 11.74) days in patients with symptom onset ≤3 days, for rilematovir 500 mg, 80 mg, and placebo, respectively. KM estimates of median (90% CI) time to resolution of key RSV symptoms were 7.1 (5.03; 11.43), 7.6 (5.93; 8.32), and 9.6 (5.95; 14.00) days for rilematovir 500 mg, 80 mg, and placebo, respectively; and in patients with symptom onset ≤3 days, median 8.0, 7.6, and 11.8 days, respectively. DISCUSSION: Rilematovir use, initiated early, suggests a potential clinical benefit in RSV-infected adults, with data supporting development of RSV therapeutic options. TRIAL REGISTRATION: This study is registered with clinicaltrials.gov (NCT03379675).

Physicians' Perception of Oral Nutritional Supplement Acceptance and Tolerability in Malnourished Outpatients: PerceptiONS Study.

Malnutrition is a common condition associated with various pathologies such as infections, neoplasms and digestive system disorders. Patients can be managed using different strategies, which include dietary modifications or oral nutritional supplements (ONS). It is important to promote good ONS adherence in order to attain clinical efficacy and cost-effectiveness. Several factors (amount, type, duration and tolerability) may have an impact on ONS adherence. PerceptiONS is a descriptive, cross-sectional observational study based on an ad hoc electronic survey designed to explore physicians' perception of malnourished outpatients prescribed ONS. The survey considered adherence, acceptance/satisfaction, tolerability and benefits within the context of Spain's healthcare system. The perceptions of 548 physicians regarding the experience of 2516 patients were analyzed. From the physicians' perspective, 57.11% of patients adhered to over 75% of the prescribed ONS. The organoleptic properties of ONS represented the aspect with the most positive impact on adherence, with smell (43.72%) ranking as the top characteristic. In general, patients were satisfied (90.10%) with the ONS, with their related benefits (88.51%) and their organoleptic properties (90.42%), and accepted ONS in their daily diet (88.63%). ONS improved patients' general condition (87.04%), quality of life (QoL) (81.96%) and vitality/energy (81.28%). Physicians would prescribe the same ONS again in 96.4% of the cases.

Post-acute COVID-19 symptom risk in hospitalized and non-hospitalized COVID-19 survivors: A systematic review and meta-analysis.

Background: Post-acute coronavirus disease 2019 (COVID-19) symptoms occurred in most of the COVID-19 survivors. However, few studies have examined the issue of whether hospitalization results in different post-acute COVID-19 symptom risks. This study aimed to compare potential COVID-19 long-term effects in hospitalized and non-hospitalized COVID-19 survivors. Methods: This study is designed as a systematic review and meta-analysis of observational studies. A systematic search of six databases was performed for identifying articles published from inception until April 20th, 2022, which compared post-acute COVID-19 symptom risk in hospitalized and non-hospitalized COVID-19 survivors using a predesigned search strategy included terms for SARS-CoV-2 (eg, COVID, coronavirus, and 2019-nCoV), post-acute COVID-19 Syndrome (eg, post-COVID, post COVID conditions, chronic COVID symptom, long COVID, long COVID symptom, long-haul COVID, COVID sequelae, convalescence, and persistent COVID symptom), and hospitalization (hospitalized, in hospital, and home-isolated). The present meta-analysis was conducted according to The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement using R software 4.1.3 to create forest plots. Q statistics and the I 2 index were used to evaluate heterogeneity in this meta-analysis. Results: Six observational studies conducted in Spain, Austria, Switzerland, Canada, and the USA involving 419 hospitalized and 742 non-hospitalized COVID-19 survivors were included. The number of COVID-19 survivors in included studies ranged from 63 to 431, and follow-up data were collected through visits in four studies and another two used an electronic questionnaire, visit and telephone, respectively. Significant increase in the risks of long dyspnea (OR = 3.18, 95% CI = 1.90-5.32), anxiety (OR = 3.09, 95% CI = 1.47-6.47), myalgia (OR = 2.33, 95% CI = 1.02-5.33), and hair loss (OR = 2.76, 95% CI = 1.07-7.12) risk were found in hospitalized COVID-19 survivors compared with outpatients. Conversely, persisting ageusia risk was significantly reduced in hospitalized COVID-19 survivors than in non-hospitalized patients. Conclusion: The findings suggested that special attention and patient-centered rehabilitation service based on a needs survey should be provided for hospitalized COVID-19 survivors who experienced high post-acute COVID-19 symptoms risk.

Post-COVID Symptoms in Occupational Cohorts: Effects on Health and Work Ability.

Post-acute COVID-19 syndrome is frequently observed in workers and has a substantial impact on work ability. We conducted a health promotion program to identify cases of post-COVID syndrome, analyze the distribution of symptoms and their association with work ability. Of the 1422 workers who underwent routine medical examination in 2021, 1378 agreed to participate. Among the latter, 164 had contracted SARS-CoV-2 and 115 (70% of those who were infected) had persistent symptoms. A cluster analysis showed that most of the post-COVID syndrome cases were characterized by sensory disturbances (anosmia and dysgeusia) and fatigue (weakness, fatigability, tiredness). In one-fifth of these cases, additional symptoms included dyspnea, tachycardia, headache, sleep disturbances, anxiety, and muscle aches. Workers with post-COVID were found to have poorer quality sleep, increased fatigue, anxiety, depression, and decreased work ability compared with workers whose symptoms had rapidly disappeared. It is important for the occupational physician to diagnose post-COVID syndrome in the workplace since this condition may require a temporary reduction in work tasks and supportive treatment.

Mild SARS-CoV-2 infection results in long-lasting microbiota instability.

Viruses targeting mammalian cells can indirectly alter the gut microbiota, potentially compounding their phenotypic effects. Multiple studies have observed a disrupted gut microbiota in severe cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that require hospitalization. Yet, despite demographic shifts in disease severity resulting in a large and continuing burden of non-hospitalized infections, we still know very little about the impact of mild SARS-CoV-2 infection on the gut microbiota in the outpatient setting. To address this knowledge gap, we longitudinally sampled 14 SARS-CoV-2-positive subjects who remained outpatient and 4 household controls. SARS-CoV-2 cases exhibited a significantly less stable gut microbiota relative to controls. These results were confirmed and extended in the K18-humanized angiotensin-converting enzyme 2 mouse model, which is susceptible to SARS-CoV-2 infection. All of the tested SARS-CoV-2 variants significantly disrupted the mouse gut microbiota, including USA-WA1/2020 (the original variant detected in the USA), Delta, and Omicron. Surprisingly, despite the fact that the Omicron variant caused the least severe symptoms in mice, it destabilized the gut microbiota and led to a significant depletion in Akkermansia muciniphila. Furthermore, exposure of wild-type C57BL/6J mice to SARS-CoV-2 disrupted the gut microbiota in the absence of severe lung pathology. IMPORTANCE Taken together, our results demonstrate that even mild cases of SARS-CoV-2 can disrupt gut microbial ecology. Our findings in non-hospitalized individuals are consistent with studies of hospitalized patients, in that reproducible shifts in gut microbial taxonomic abundance in response to SARS-CoV-2 have been difficult to identify. Instead, we report a long-lasting instability in the gut microbiota. Surprisingly, our mouse experiments revealed an impact of the Omicron variant, despite producing the least severe symptoms in genetically susceptible mice, suggesting that despite the continued evolution of SARS-CoV-2, it has retained its ability to perturb the intestinal mucosa. These results will hopefully renew efforts to study the mechanisms through which Omicron and future SARS-CoV-2 variants alter gastrointestinal physiology, while also considering the potentially broad consequences of SARS-CoV-2-induced microbiota instability for host health and disease.

The Greifswald Post COVID Rehabilitation Study and Research (PoCoRe)-Study Design, Characteristics and Evaluation Tools.

(1) Background: COVID-19 is often associated with significant long-term symptoms and disability, i.e., the long/post-COVID syndrome (PCS). Even after presumably mild COVID-19 infections, an increasing number of patients seek medical help for these long-term sequelae, which can affect various organ systems. The pathogenesis of PCS is not yet understood. Therapy has so far been limited to symptomatic treatment. The Greifswald Post COVID Rehabilitation Study (PoCoRe) aims to follow and deeply phenotype outpatients with PCS in the long term, taking a holistic and comprehensive approach to the analysis of their symptoms, signs and biomarkers. (2) Methods: Post-COVID outpatients are screened for symptoms in different organ systems with a standardized medical history, clinical examination, various questionnaires as well as physical and cardiopulmonary function tests. In addition, biomaterials are collected for the analysis of immunomodulators, cytokines, chemokines, proteome patterns as well as specific (auto)antibodies. Patients are treated according to their individual needs, adhering to the current standard of care. PoCoRe's overall aim is to optimize diagnostics and therapy in PCS patients.

Mid-term MRI evaluation reveals microstructural white matter alterations in COVID-19 fully recovered subjects with anosmia presentation.

Background: Little is still known about the mid/long-term effects of coronavirus disease 2019 (COVID-19) on the brain, especially in subjects who have never been hospitalized due to the infection. In this neuroimaging exploratory study, we analyzed the medium-term effect of COVID-19 on the brain of people who recovered from COVID-19, experienced anosmia during the acute phase of the disease, and have never been hospitalized due to SARS-Co-V-2 infection. Methods: Forty-three individuals who had (COV+, n = 22) or had not (COV-, n = 21) been infected with SARS-Co-V-2 were included in the study; the two groups were age- and sex-matched and were investigated using 3T magnetic resonance imaging (MRI). Gray matter (GM) volume, white matter (WM) hyperintensity volume, WM microstrutural integrity (i.e. fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AD], radial diffusivity [RD]) and cerebral blood flow (CBF) differences between the two groups were tested with either analysis of covariance or voxel-wise analyses. Results were family wise error (FWE) corrected. Results: No significant differences between COV+ and COV- groups were observed in terms of GM volume, WM hyperintensity volume, and CBF. Conversely, local WM microstructural alterations were detected in COV+ when compared with COV- with tract-based spatial statistics. Specifically, COV+ showed lower FA (pFWE-peak = 0.035) and higher RD (pFWE-peak = 0.038) than COV- in several WM regions. Conclusion: COVID-19 may produce mid/long-term microstructural effect on the brain, even in case of mild-to-moderate disease not requiring hospitalization. Further investigation and additional follow-ups are warranted to assess if the alterations reported in this study totally recover over time. As brain alterations could increase the risk of cognitive decline, greater knowledge of their trajectories is crucial to aid neurorehabilitation treatments.

Inflammatory Markers, Pulmonary Function, and Clinical Symptoms in Acute COVID-19 Among Non-Hospitalized Adolescents and Young Adults.

Summary: Mild, subacute COVID-19 in young people show inflammatory enhancement, but normal pulmonary function. Inflammatory markers are associated with age and male sex, whereas clinical symptoms are associated with age and female sex, but not with objective disease markers. Background: Coronavirus Disease 2019 (COVID-19) is widespread among adolescents and young adults across the globe. The present study aimed to compare inflammatory markers, pulmonary function and clinical symptoms across non-hospitalized, 12 - 25 years old COVID-19 cases and non-COVID-19 controls, and to investigate associations between inflammatory markers, clinical symptoms, pulmonary function and background variables in the COVID-19 group. Methods: The present paper presents baseline data from an ongoing longitudinal observational cohort study (Long-Term Effects of COVID-19 in Adolescents, LoTECA, ClinicalTrials ID: NCT04686734). A total of 31 plasma cytokines and complement activation products were assayed by multiplex and ELISA methodologies. Pulmonary function and clinical symptoms were investigated by spirometry and questionnaires, respectively. Results: A total of 405 COVID-19 cases and 111 non-COVID-19 controls were included. The COVID-19 group had significantly higher plasma levels of IL-1ß, IL-4, IL-7, IL-8, IL-12, TNF, IP-10, eotaxin, GM-CSF, bFGF, complement TCC and C3bc, and significantly lower levels of IL-13 and MIP-1α, as compared to controls. Spirometry did not detect any significant differences across the groups. IL-4, IL-7, TNF and eotaxin were negatively associated with female sex; eotaxin and IL-4 were positively associated with age. Clinical symptoms were positively associated with female sex and age, but not with objective disease markers. Conclusions: Among non-hospitalized adolescents and young adults with COVID-19 there was significant alterations of plasma inflammatory markers in the subacute stage of the infection. Still, pulmonary function was normal. Clinical symptoms were independent of inflammatory and pulmonary function markers, but positively associated with age and female sex.

Nutrition Risk Screening and Related Factors Analysis of Non-hospitalized Cancer Survivors: A Nationwide Online Survey in China.

Purposes: This study investigated the nutritional problems and risks of Chinese non-hospitalized cancer survivors through an online survey. Methods: The survey included nutritional and clinical questions distributed to non-hospitalized cancer survivors. All data were screened and analyzed with strict quality control. Nutrition Risk Screening-2002 (NRS-2002) was adopted and the related factors were analyzed. Results: Six thousand six hundred eighty-five questionnaires were included. The prevalence of nutritional risk was 33.9%, which varied according to age, sex, cancer type, TNM staging, oncologic treatment, time interval since last treatment, etc. In the regression analysis, nutritional risk was associated with age, TNM staging, and nutrition support. Patients with leukemia and digestive cancer had the highest NRS-2002 score (3.33 ± 1.45 and 3.25 ± 1.61); the prevalence of nutritional risk (NRS-2002 ≥ 3) was 66.7 and 55.1%, respectively. Patients with a higher TNM stage had higher NRS-2002 scores in non-digestive cancer, which was not seen in digestive cancer. Among digestive, bone, nervous, and respiratory cancer patients, the NRS-2002 score mainly consisted of "impaired nutritional status," which coincided with the "disease severity score" in leukemia patients. Nutrition intervention was achieved in 79.7 and 15.2% of patients with nutritional risk and no risk. Of the patients, 60.3% exhibited confusion about nutritional problems, but only 25.1% had professional counseling. Conclusions: Regular nutritional risk screening, assessment, and monitoring are needed to cover non-hospitalized cancer survivors to provide nutrition intervention for better clinical outcome and quality of life. By online survey, the nutritional risk of non-hospitalized cancer survivors was found high in China, but the nutrition support or professional consultation were not desirable. The composition of nutritional risk should also be aware of.

Liver tests abnormalities with licensed antiviral drugs for COVID-19: a narrative review.

INTRODUCTION: Liver involvement in COVID-19 is multifactorial, and the three potential mechanisms are direct hepatocyte viral damage, vascular or cellular damage during the cytokine storm of severe COVID-19 and drug-induced liver injury. To date, three antivirals are licensed for the treatment of COVID-19 by most guidelines: remdesivir, molnupiravir, and ritonavir-boosted nirmatrelvir. AREAS COVERED: We performed a narrative review about the hepatic safety profile of the three antivirals licensed for COVID-19 treatment. We used data about hepatobiliary adverse events from English-language randomized clinical trials (RCTs). EXPERT OPINION: Remdesivir was found to be potentially hepatotoxic, and liver biochemistry abnormalities were common (2-34%) but mild and reversible. Molnupiravir exhibits a favorable safety profile and the increase in aminotransferases was usually mild and reversible (up to 11% of patients in one study). Ritonavir-boosted nirmatrelvir is potentially hepatotoxic, but in the only phase 3 RCT there were no safety issues and aspartate aminotransferase/alanine aminotransferase levels increase did not exceed 2.4% of patients. All antivirals have a favorable safety profile, but they are not sufficiently studied in patients with underlying chronic kidney or liver disease. In this special populations, antivirals should be used with caution and careful monitoring during treatment should be pursued on a case-by-case basis.