Onset Of COVID-19 Symptoms Research Articles

Convalescent anti-SARS-CoV-2 plasma for the treatment of patients with COVID-19: a retrospective study RESCOVID-19

PurposeConvalescent plasma (CP) collected from people who recovered from COVID-19 became a rapidly available treatment modality in numerous countries, including the Czech Republic. The aims of our study were to evaluate the effectiveness and safety of CP in the treatment of COVID-19.MethodsThis retrospective observational study involved six Czech hospitals. This study enrolled patients with and without CP treatment who were hospitalized between April 2020 and April 2021. Propensity score matching and logistic regression analysis were performed to evaluate the influence of CP administration and its timing on the in-hospital survival of COVID-19 patients.ResultsA total of 1,498 patients were enrolled in the study; 406 (27%) were administered CP, and 1,092 (73%) were not treated with CP. The propensity score-matched control group consisted of 1,218 subjects. The survival of patients treated with CP was 79%, while that of patients in the matched control group was 62% (P<0.001). Moreover, the chance of survival was significantly greater when CP was administered within three days after the onset of COVID-19 symptoms than when CP was administered after four or more days (87% vs. 76%, P <0.001). In addition, adverse effects related to CP administration were recorded in only 2% of patients and were considered mild in all patients.ConclusionsOur study demonstrated that the administration of CP was safe and possibly associated with positive effects that were more pronounced if CP was administered within the first three days after the onset of COVID-19 symptoms.

Outcome differences of starting Paxlovid for COVID-19 within or after five days of symptoms onset in the elderly: a retrospective study.

The study aimed to compare the outcomes of nirmatrelvir and ritonavir drug combination (Paxlovid) therapy in patients who received treatment within or after five days of COVID-19 confirmed in the elderly. This was a single-center, retrospective cohort study of older COVID-19 patients (≥ 60 years) admitted from April 7 to May 30, 2022. Patients were categorized into the EP group (starting Paxlovid within five days) and the LP group (starting Paxlovid after five days) following symptoms onset. Length of stay and positive SARS-CoV-2 duration were compared between the two groups. Severe case conversion from mild and moderate COVID-19 patients were also analyzed. In total, 273 patients were included: 137 in the EP group and 136 in the LP group. Compared to the LP group, the EP group had a significantly shorter length of stay (12.4 vs. 14.7 days, p = 0.001) and positive SARS-CoV-2 duration (11.7 vs. 15.8 days, p < 0.001). The EP group had lower severe case conversion (4.4% vs. 15.4%, p = 0.002). Additionally, abnormal IL-6 and lower lymphocyte count indicated increased length of stay. Older age was associated with a decreased risk in SARS-CoV-2 negative test (HR = 0.98) and an increased risk in severe case conversion (OR = 1.11). Starting Paxlovid within five days of COVID-19 symptoms onset reduced the length of stay and SARS-CoV-2 duration compared to initiating treatment after five days. While severe case conversion among mild COVID-19 patients might be comparable whether starting Paxlovid within or after five days.

Rapid intra-host diversification and evolution of SARS-CoV-2 in advanced HIV infection

Previous studies have linked the evolution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic variants to persistent infections in people with immunocompromising conditions, but the processes responsible for these observations are incompletely understood. Here we use high-throughput, single-genome amplification and sequencing (HT-SGS) to sequence SARS-CoV-2 spike genes from people with HIV (PWH, n = 22) and people without HIV (PWOH, n = 25). In PWOH and PWH with CD4 T cell counts (i.e., CD4 counts) ≥ 200 cells/μL, we find that most SARS-CoV-2 genomes sampled in each person share one spike sequence. By contrast, in people with advanced HIV infection (i.e., CD4 counts < 200 cells/μL), HT-SGS reveals a median of 46 distinct linked groupings of spike mutations per person. Elevated intra-host spike diversity in people with advanced HIV infection is detected immediately after COVID-19 symptom onset, and early intra-host spike diversity predicts SARS-CoV-2 shedding duration among PWH. Analysis of longitudinal timepoints reveals rapid fluctuations in spike sequence populations, replacement of founder sequences by groups of new haplotypes, and positive selection at functionally important residues. These findings demonstrate remarkable intra-host genetic diversity of SARS-CoV-2 in advanced HIV infection and suggest that adaptive intra-host SARS-CoV-2 evolution in this setting may contribute to the emergence of new variants of concern.

Dermatologic manifestations of patients with severe and non-severe COVID-19 infection: A cross-sectional study

Introduction: Since the emergence of COVID-19 in late 2019, multiple concerns have been raised regarding the unknown nature of the disease, including dermatologic complications. In this study, we discussed dermatologic manifestations of patients with COVID-19 infection who visited our clinic. Methods: Eighty- six patients were involved based on our inclusion and exclusion criteria (50 female and 36 male). All patients with definite diagnosis of COVID-19 who were referred to our dermatologic clinic were enrolled in this cross-sectional study. Only lesions which occurred 1 week prior to or 3 months after first COVID-19 symptoms were included. The photographs of all lesions were independently reviewed by four experienced dermatologists and an infectious disease specialist to reach the objectives stated above. Qualitative data presented as frequency (%) and compared using chi-squared or Fisher’s exact test, and quantitative data presented as mean±SD or median (IQR) based on normality, with P value≤0.05 considered statistically significant. Results: Eighty- six patients were enrolled in the study (mean±SD age=36.95±17.78). Eighteen specific types of dermatologic complications were seen. The most common lesions included maculopapular rash and scalp hair loss. The only lesions with a statistically significant difference regarding COVID-19 symptom onset time were maculopapular rash, telogen effluvium, and papular urticaria. The only lesions with statistically significant difference regarding COVID-19 severity were maculopapular rash, telogen effluvium, and urticaria. Conclusion: Our study revealed that a wide range of skin lesions may occur in patients with COVID-19. We found a statistically significant relation between disease severity and certain dermatologic manifestations.

Early inflammatory profiles predict maximal disease severity in COVID-19: An unsupervised cluster analysis

BackgroundThe inflammatory changes that underlie the heterogeneous presentations of COVID-19 remain incompletely understood. In this study we aimed to identify inflammatory profiles that precede the development of severe COVID-19, that could serve as targets for optimised delivery of immunomodulatory therapies and provide insights for the development of new therapies. MethodsWe included individuals sampled <10 days from COVID-19 symptom onset, recruited from both inpatient and outpatient settings. We measured 61 biomarkers in plasma, including markers of innate immune and T cell activation, coagulation, tissue repair and lung injury. We used principal component analysis and hierarchical clustering to derive biomarker clusters, and ordinal logistic regression to explore associations between cluster membership and maximal disease severity, adjusting for known risk factors for severe COVID-19. ResultsIn 312 individuals, median (IQR) 7 (4–9) days from symptom onset, we found four clusters. Cluster 1 was characterised by low overall inflammation, cluster 2 was characterised by higher levels of growth factors and markers of endothelial activation (EGF, VEGF, PDGF, TGFα, PAI-1 and p-selectin). Cluster 3 and 4 both had higher overall inflammation. Cluster 4 had the highest levels of most markers including markers of innate immune activation (IL6, procalcitonin, CRP, TNFα), and coagulation (D-dimer, TPO), in contrast cluster 3 had the highest levels of alveolar epithelial injury markers (RAGE, ST2), but relative downregulation of growth factors and endothelial activation markers, suggesting a dysfunctional inflammatory pattern. In unadjusted and adjusted analysis, compared to cluster 1, cluster 3 had the highest odds of progressing to more severe disease (unadjusted OR (95%CI) 9.02 (4.53–17.96), adjusted OR (95%CI) 6.02 (2.70–13.39)). ConclusionEarly inflammatory profiles predicted subsequent maximal disease severity independent of risk factors for severe COVID-19. A cluster with downregulation of growth factors and endothelial activation markers, and early evidence of alveolar epithelial injury, had the highest risk of severe COVID-19.

Safety and Efficacy of SAB-185 for Non-hospitalized Adults with COVID-19: A Randomized Clinical Trial.

To address the need for novel COVID-19 therapies, we evaluated the fully-human polyclonal antibody product SAB-185 in a phase 3 clinical trial. Non-hospitalized high-risk adults within 7 days of COVID-19 symptom onset were randomized 1:1 to open-label SAB-185 3,840 units/kg or casirivimab/imdevimab 1200 mg. Non-inferiority comparison was undertaken for the pre-Omicron population (casirivimab/imdevimab expected to be fully active) and superiority comparison for the Omicron population (casirivimab/imdevimab not expected to be active). Primary outcomes were the composite of all-cause hospitalizations/deaths and grade ≥3 treatment-emergent adverse events (TEAEs) through day 28. Secondary outcomes included time to sustained symptom improvement and resolution. Enrollment was terminated early due to low hospitalization/death rates upon Omicron emergence. 733 adults were randomized, 255 included in pre-Omicron and 392 in Omicron analysis populations. Hospitalizations/deaths occurred in 6 (5.0%) and 3 (2.2%) of pre-Omicron SAB-185 and casirivimab/imdevimab arms, respectively (absolute difference [95% CI] 2.7% [-2.3%, 8.6%]), inconclusive for non-inferiority; and 5 (2.5%) versus 3 (1.5%) (absolute difference 1.0% [-2.3%, 4.5%]) for Omicron. Risk ratios for grade ≥3 TEAEs were 0.94 [0.52, 1.71] (pre-Omicron) and 1.71 [0.96, 3.07] (Omicron). Time to symptom improvement and resolution were shorter for SAB-185, median 11 vs 14 (pre-Omicron) and 11 vs 13 days (Omicron) (symptom improvement), and 16 vs 24 days and 18 vs >25 days (symptom resolution), p<0.05 for symptom resolution for Omicron only. SAB-185 had an acceptable safety profile with faster symptom resolution in the Omicron population. Additional studies are needed to characterize its efficacy for COVID-19.

In-hospital survival of critically ill COVID-19 patients treated with glucocorticoids: a multicenter real-world data study

The COVID-19 pandemic has posed a major challenge to healthcare systems globally. Millions of people have been infected, and millions of deaths have been reported worldwide. Glucocorticoids have attracted worldwide attention for their potential efficacy in the treatment of COVID-19. Various glucocorticoids with different dosages and treatment durations have been studied in patients with different severities, with a suitable dosage and treatment duration not yet defined. This study aimed to investigate whether in-hospital survival differs between critically ill patients treated with low-dose glucocorticoids, high-dose glucocorticoids or no glucocorticoids. All critically ill patients admitted to the intensive care unit of the Charité Hospital—Universitätsmedizin Berlin between February 2020 and December 2021 with COVID-19 pneumonia receiving supplemental oxygen were eligible to participate in this multicenter real-world data study. Patients were retrospectively assigned to one of three groups: the high corticosteroid dose (HighC) group (receiving 6 mg parenteral dexamethasone or an equivalent corticosteroid dosage for ten days), the low corticosteroid dose (LowC) group (receiving less than 6 mg parenteral dexamethasone or an equivalent corticosteroid dosage for ten days), or the no corticosteroid (NoC) group. Overall survival and risk effects were compared among groups within the total observation period, as well as at 35 days after the onset of COVID-19 symptoms. Adjusted multivariable Cox proportional hazard regression analysis was performed to compare the risk of death between the treatment groups. Out of 1561 critically ill COVID-19 patients, 1014 were included in the baseline analysis. In the survival study, 1009 patients were assigned to the NoC (n = 346), HighC (n = 552), or LowC group (n = 111). The baseline characteristics were balanced between groups, except for age, BMI, APACHE II score, SOFA and SAPS II. While the 35-day survival did not show any differences, a landmark analysis of the patients surviving beyond 35 days revealed differences between groups. The restricted mean survival time was 112 days in the LowC group [95% CI: 97 – 128], 133 days in the HighC group [95% CI: 124 – 141] and 144 days in the NoC group [95% CI: 121 – 167]. The multivariable-adjusted Cox proportional hazard analysis indicated that, regardless of age, sex, health status or invasive oxygenation, a low-dose treatment increased the hazard of death of critically ill COVID-19 patients by a factor of 2.09 ([95% CI: 0.99, 4.4], p = 0.05) and a high-dose corticosteroid treatment increased the risk by a factor of 1.07 ([95% CI: 0.53, 2.15], p = 0.85) compared to no treatment with glucocorticoids. The analysis reveals that corticosteroid treatment does not influence the survival of critically ill COVID-19 patients in the intensive care unit within 35 days. Our evaluations further suggest that regardless of ventilation status, the decision-making process for administering corticosteroid therapy should account for the individual severity of the illness.

RNA Polymerase Inhibitor Enisamium for Treatment of Moderate COVID-19 Patients: A Randomized, Placebo-Controlled, Multicenter, Double-Blind Phase 3 Clinical Trial.

Enisamium is an orally available therapeutic that inhibits influenza A virus and SARS-CoV-2 replication. We evaluated the clinical efficacy of enisamium treatment combined with standard care in adult, hospitalized patients with moderate COVID-19 requiring external oxygen. Hospitalized patients with laboratory-confirmed SARS-CoV-2 infection were randomly assigned to receive either enisamium (500 mg per dose, four times a day) or a placebo. The primary outcome was an improvement of at least two points on an eight-point severity rating (SR) scale within 29 days of randomization. We initially set out to study the effect of enisamium on patients with a baseline SR of 4 or 5. However, because the study was started early in the COVID-19 pandemic, and COVID-19 had been insufficiently studied at the start of our study, an interim analysis was performed alongside a conditional power analysis in order to ensure patient safety and assess whether the treatment was likely to be beneficial for one or both groups. Following this analysis, a beneficial effect was observed for patients with an SR of 4 only, i.e., patients with moderate COVID-19 requiring supplementary oxygen. The study was continued for these COVID-19 patients. Overall, a total of 592 patients were enrolled and randomized between May 2020 and March 2021. Patients with a baseline SR of 4 were divided into two groups: 142 (49.8%) were assigned to the enisamium group and 143 (50.2%) to the placebo group. An analysis of the population showed that if patients were treated within 4 days of the onset of COVID-19 symptoms (n = 33), the median time to improvement was 8 days for the enisamium group and 13 days for the placebo group (p = 0.005). For patients treated within 10 days of the onset of COVID-19 symptoms (n = 154), the median time to improvement was 10 days for the enisamium group and 12 days for the placebo group (p = 0.002). Our findings suggest that enisamium is safe to use with COVID-19 patients, and that the observed clinical benefit of enisamium is worth reporting and studying in detail.

Gustatory dysfunction and long COVID in Chinese patients with COVID-19: A 6-month follow-up study.

To evaluate long COVID of gustatory dysfunction and the associated risk factors regarding onset and recovery in Chinese patients. We conducted a cross-sectional study of patients with SARS-CoV-2 Omicron infection at Changxing Mobile Cabin Hospital in Shanghai, China, from March to May 2022. A prospective follow-up of patients with gustatory dysfunction was conducted at 6 months after discharge. In total, 18.48% (241/1304) reported gustatory dysfunction. The 6-month follow-up response rate was 89.63% (216/241) and 74.02% recovered their taste sense within 1-3 weeks. A total of 20.37% of patients (44/216) presented with long COVID. Symptoms persisted for 12 patients (5.56%) after 6 months. Having multiple taste impairments (OR, 2.364; 95% CI, 1.286-4.348; p = 0.006) was associated with a higher risk of gustatory dysfunction with long COVID. Having received a COVID-19 vaccine booster was positively associated with taste sensation recovery (HR, 1.344; 95% CI, 1.012-1.785; p = 0.041). About 20.37% of patients with COVID-19 might develop long COVID of gustatory dysfunction and 5.56% with persisting changes in their sense of taste. Most patients recovered taste sensations within 1-3 weeks after COVID-19 symptom onset and receiving a booster shot of the COVID-19 vaccine presented a protective effect on the taste sensation recovery.

Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19

Persistent symptoms following SARS-CoV-2 infection are increasingly reported, although the drivers of post-acute sequelae (PASC) of COVID-19 are unclear. Here we assessed 214 individuals infected with SARS-CoV-2, with varying disease severity, for one year from COVID-19 symptom onset to determine the early correlates of PASC. A multivariate signature detected beyond two weeks of disease, encompassing unresolving inflammation, anemia, low serum iron, altered iron-homeostasis gene expression and emerging stress erythropoiesis; differentiated those who reported PASC months later, irrespective of COVID-19 severity. A whole-blood heme-metabolism signature, enriched in hospitalized patients at month 1–3 post onset, coincided with pronounced iron-deficient reticulocytosis. Lymphopenia and low numbers of dendritic cells persisted in those with PASC, and single-cell analysis reported iron maldistribution, suggesting monocyte iron loading and increased iron demand in proliferating lymphocytes. Thus, defects in iron homeostasis, dysregulated erythropoiesis and immune dysfunction due to COVID-19 possibly contribute to inefficient oxygen transport, inflammatory disequilibrium and persisting symptomatology, and may be therapeutically tractable.

Comparison of Forced Expiratory Flow (FEF) 25-75% between Post-COVID-19 Patients with Different Severity at Universitas Gadjah Mada Academic Hospital

Introduction: Shortness of breath is the most distressing long COVID-19 symptom associated with the decline of small airway function, as shown by a decrease in forced expiratory flow (FEF) 25-75% value in the spirometry test. This study aimed to compare FEF 25-75% values as a predictor of small airway disease between mild-moderate and severe-critical long COVID-19 patients. Methods: This study used a prospective cohort design that included 24 post-hospitalized COVID-19 patients who came to the long COVID-19 clinic at Universitas Gadjah Mada Academic Hospital (UGM AH), Yogyakarta. The subjects were divided into mild-moderate and severe-critical groups based on the World Health Organization (WHO) classification. The subjects were tested for spirometry three months after the onset of COVID-19 symptoms. The comparison of both severity groups used the percent prediction of FEF 25-75% spirometry results. The value was interpreted as abnormal if the predicted FEF 25-75% value was below 65%. Results: There were three (25%) and two (16.67%) subjects with FEF 25-75% predicted below normal values in the mild-moderate and severe-critical groups consecutively, which showed a decline in small airway function. This study showed no statistically significant differences (p-value = 0.882) between the means of FEF 25-75% predicted values of the two groups. Conclusion: A small proportion of post-COVID-19 syndrome patients had small airway disease, and there were no statistical differences in small airway function between the groups.

Cognitive functioning in patients with neuro-PASC: the role of fatigue, mood, and hospitalization status.

This study sought to characterize cognitive functioning in patients with neurological post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC) and investigate the association of subjective and objective functioning along with other relevant factors with prior hospitalization for COVID-19. Participants were 106 adult outpatients with Neuro-PASC referred for abbreviated neuropsychological assessment after scoring worse than one standard deviation below the mean on cognitive screening. Of these patients, 23 had been hospitalized and 83 had not been hospitalized for COVID-19. Subjective cognitive impairment was evaluated with the self-report cognition subscale from the Patient-Reported Outcome Measurement Information System. Objective cognitive performance was assessed using a composite score derived from multiple standardized cognitive measures. Other relevant factors, including fatigue and depression/mood symptoms, were assessed via the Patient-Reported Outcome Measurement Information System. Subjective cognitive impairment measures exceeded the minimal difficulties noted on objective tests and were associated with depression/mood symptoms as well as fatigue. However, fatigue independently explained the most variance (17.51%) in patients' subjective cognitive ratings. When adjusting for fatigue and time since onset of COVID-19 symptoms, neither objective nor subjective impairment were associated with prior hospitalization for COVID-19. Findings suggest that abbreviated neuropsychological assessment may not reveal objective difficulties beyond initial cognitive screening in patients with Neuro-PASC. However, subjective cognitive concerns may persist irrespective of hospitalization status, and are likely influenced by fatigue and depression/mood symptoms. The impact of concomitant management of fatigue and mood in patients with Neuro-PASC who report cognitive concerns deserve further study.

The prevalence of long COVID-19 syndrome in hospitalized patients with COVID-19 pneumonia.

Long COVID affects millions of individuals worldwide with a wide range of persistent symptoms. Pathogenesis, prevalence and clinical approach of this syndrome remain not well characterized.The aim of the study is the estimation of prevalence of long-COVID and identification of possible risk factors. This is an observational prospective study including COVID-19 patients hospitalized at the Department of Infectious Diseases of the University General Hospital of Alexandroupolis (Greece). Eligible COVID-19 patients were interviewed and examined 6, 12 and 18 months after COVID-19 symptoms onset and hospital discharge in order to evaluate the prevalence and consequences of long-COVID symptoms. A total number of 995 patients were included. The median age at discharge was 55 years and 53% of patients were retired. The majority was males (57%). Vaccination against SARS-CoV-2 was completed in 52% (n=517) COVID-19 patients. More than 40% of COVID-19 patients had at least one symptom at 18 months after hospitalization. Intravenous antiviral 0treatment with remdesivir and complete vaccination status were found to lead to lower rates of Long-COVID. More studies in larger patient cohorts are needed in order to identify the underlying biological mechanisms of long-COVID and create effective interventions for prevention and treatment.

Optimal timing of nirmatrelvir/ritonavir treatment after COVID-19 symptom onset or diagnosis: target trial emulation

Reports of symptomatic rebound and/or test re-positivity among COVID-19 patients following the standard five-day treatment course of nirmatrelvir/ritonavir have sparked debates regarding optimal treatment timing and dosage. It is unclear whether initiating nirmatrelvir/ritonavir immediately after symptom onset would improve clinical outcomes and/or lead to post-treatment viral burden rebound due to inadequate viral clearance during treatment. Here we show that, by emulating a randomized target trial using real-world electronic medical record data from all 87,070 adult users of nirmatrelvir/ritonavir in Hong Kong between 16th March 2022 and 15th January 2023, early initiation of nirmatrelvir/ritonavir treatment (0 to 1 days after symptom onset or diagnosis) significantly reduced the incidence of 28-day all-cause mortality and hospitalization compared to delayed initiation (2 or more days) (absolute risk reduction [ARR]: 1.50% (95% confidence interval 1.17-1.80%); relative risk [RR]: 0.77 (0.73, 0.82)), but may be associated with a significant elevated risk of viral burden rebound (ARR: −1.08% (−1.55%, −0.46%)), although the latter estimates were associated with high uncertainty due to limited sample sizes. As such, patients should continue to initiate nirmatrelvir/ritonavir early after symptom onset or diagnosis to better protect against the more serious outcomes of hospitalization and mortality.

High frequency of endoluminal thrombus in patients with ischaemic stroke following AARS-CoV-2 infection

BackgroundIschaemic stroke may be a major complication of SARS-CoV-2 infection. Studying and characterising the different aetiological subtypes, clinical characteristics, and functional outcomes may be valuable in guiding patient selection for optimal management and treatment. MethodsData were collected retrospectively on consecutive patients with COVID-19 who developed acute focal brain ischaemia (between 1 March and 19 April 2020) at a tertiary university hospital in Madrid (Spain). ResultsDuring the study period, 1594 patients were diagnosed with COVID-19. We found 22 patients with ischaemic stroke (1.38%), 6 of whom did not meet the inclusion criteria. The remaining 16 patients were included in the study (15 cases of ischaemic stroke and one case of transient ischaemic attack).Median baseline National Institutes of Health Stroke Scale score was 9 (interquartile range: 16), and mean (standard deviation) age was 73 years (12.8). Twelve patients (75%) were men. Mean time from COVID-19 symptom onset to stroke onset was 13 days. Large vessel occlusion was identified in 12 patients (75%).We detected elevated levels of D-dimer in 87.5% of patients and C-reactive protein in 81.2%. The main aetiology was atherothrombotic stroke (9 patients, 56.3%), with the predominant subtype being endoluminal thrombus (5 patients, 31.2%), involving the internal carotid artery in 4 cases and the aortic arch in one. The mortality rate in our series was 44% (7 of 16 patients). ConclusionsIn patients with COVID-19, the most frequent stroke aetiology was atherothrombosis, with a high proportion of endoluminal thrombus (31.2% of patients). Our clinical and laboratory data support COVID-19–associated coagulopathy as a relevant pathophysiological mechanism for ischaemic stroke in these patients.

Oral VV116 versus placebo in patients with mild-to-moderate COVID-19 in China: a multicentre, double-blind, phase 3, randomised controlled study

Spread of SARS-CoV-2 led to a global pandemic, and there remains unmet medical needs in the treatment of Omicron infections. VV116, an oral antiviral agent that has potent activity against SARS-CoV-2, was compared with a placebo in this phase 3 study to investigate its efficacy and safety in patients with mild-to-moderate COVID-19. This multicentre, double-blind, phase 3, randomised controlled study enrolled adults in hospitals for infectious diseases and tertiary general hospitals in China. Eligible patients were randomly assigned in a 1:1 ratio using permuted block randomisation to receive oral VV116 (0·6 g every 12 h on day 1 and 0·3 g every 12 h on days 2-5) or oral placebo (on the same schedule as VV116) for 5 days. Randomisation stratification factors included SARS-CoV-2 vaccination status and the presence of high-risk factors for progression to severe COVID-19. Inclusion criteria were a positive SARS-CoV-2 test, an initial onset of COVID-19 symptoms 3 days or less before the first study dose, and a score of 2 or more for any target COVID-19-related symptoms in the 24 h before the first dose. Patients who had severe or critical COVID-19 or who had taken any antiviral drugs were excluded from the study. The primary endpoint was the time to clinical symptom resolution for 2 consecutive days. Efficacy analyses were performed on a modified intention-to-treat population, comprising all patients who received at least one dose of VV116 or placebo, tested positive for SARS-CoV-2 nucleic acid, and did not test positive for influenza virus before the first dose. Safety analyses were done on all participants who received at least one dose of VV116 or placebo. This study was registered with ClinicalTrials.gov, NCT05582629, and has been completed. A total of 1369 patients were randomly assigned to treatment groups and 1347 received either VV116 (n=674) or placebo (n=673). At the interim analysis, VV116 was superior to placebo in reducing the time to sustained clinical symptom resolution among 1229 patients (hazard ratio [HR] 1·21, 95% CI 1·04-1·40; p=0·0023). At the final analysis, a substantial reduction in time to sustained clinical symptom resolution was observed for VV116 compared with placebo among 1296 patients (HR 1·17, 95% CI 1·04-1·33; p=0·0009), consistent with the interim analysis. The incidence of adverse events was similar between groups (242 [35·9%] of 674 patients vs 283 [42·1%] of 673 patients). Among patients with mild-to-moderate COVID-19, VV116 significantly reduced the time to sustained clinical symptom resolution compared with placebo, with no observed safety concerns. Shanghai Vinnerna Biosciences, Shanghai Science and Technology Commission, and the National Key Research and Development Program of China. For the Chinese translation of the abstract see Supplementary Materials section.

Wearable Devices to Diagnose and Monitor the Progression of COVID-19 Through Heart Rate Variability Measurement: Systematic Review and Meta-Analysis.

Recent studies have linked low heart rate variability (HRV) with COVID-19, indicating that this parameter can be a marker of the onset of the disease and its severity and a predictor of mortality in infected people. Given the large number of wearable devices that capture physiological signals of the human body easily and noninvasively, several studies have used this equipment to measure the HRV of individuals and related these measures to COVID-19. The objective of this study was to assess the utility of HRV measurements obtained from wearable devices as predictive indicators of COVID-19, as well as the onset and worsening of symptoms in affected individuals. A systematic review was conducted searching the following databases up to the end of January 2023: Embase, PubMed, Web of Science, Scopus, and IEEE Xplore. Studies had to include (1) measures of HRV in patients with COVID-19 and (2) measurements involving the use of wearable devices. We also conducted a meta-analysis of these measures to reduce possible biases and increase the statistical power of the primary research. The main finding was the association between low HRV and the onset and worsening of COVID-19 symptoms. In some cases, it was possible to predict the onset of COVID-19 before a positive clinical test. The meta-analysis of studies reported that a reduction in HRV parameters is associated with COVID-19. Individuals with COVID-19 presented a reduction in the SD of the normal-to-normal interbeat intervals and root mean square of the successive differences compared with healthy individuals. The decrease in the SD of the normal-to-normal interbeat intervals was 3.25 ms (95% CI -5.34 to -1.16 ms), and the decrease in the root mean square of the successive differences was 1.24 ms (95% CI -3.71 to 1.23 ms). Wearable devices that measure changes in HRV, such as smartwatches, rings, and bracelets, provide information that allows for the identification of COVID-19 during the presymptomatic period as well as its worsening through an indirect and noninvasive self-diagnosis.

51 Trajectories and Predictors of Cognitive Change Following COVID-19

Objective:Acute cognitive complications following COVID-19 infection have been appreciated in a subset of patients since the early months of the global pandemic. Emerging data reveal that some patients go on to experience cognitive improvement, whereas others may experience further cognitive decline. We aimed to assess trajectories and predictors of cognitive change in a sample of post-COVID-19 patients.Participants and Methods:This prospective cohort study assessed longitudinal cognitive change in adults receiving care for COVID-19 in the Johns Hopkins Post-Acute COVID-19 Team (JH PACT) clinic. Participants self-administered the Digital Automated Neurobehavioral Assessment (DANA) battery of seven cognitive tests and a performance-based measure of cognitive fatigue on up to six occasions over six weeks. Improvement or decline between the first and last assessment was defined as change of &gt;1 standard deviation of the baseline mean of each outcome. Potential predictors of change included demographic features (age, sex, race/ethnicity, education), COVID-19 illness characteristics (hospitalization or ICU stay, months since symptom onset), and comorbid disease burden. Analyses included measures of central tendency, independent samples t-tests, and chi-square tests of independence.Results:Of the 36 enrolled participants, 29 (81%) completed at least one DANA assessment (M = 4.7 assessments, SD = 1.8). Those completing at least three assessments (n = 24, 66.7%) were included in the present analyses (71% female; 58% white; M age = 54 years, SD = 10.9; M education = 14.6 years, SD = 2.4; M months since COVID-19 symptom onset at recruitment = 9.8, SD = 4.7; M comorbidities = 2.8, SD = 2.0). Fatigue was the most frequently improved outcome measure, with 41.7% of participants scoring &gt;1 standard deviation above the baseline mean fatigue score at their final assessment. Among cognitive outcomes, the greatest frequency of improvement was observed on tests assessing rapid spatial processing (37.5%), processing speed (33.3%), and memory (33.3%). There were no consistent predictors of improvement, but several subtest-specific findings emerged. Specifically, (a) more comorbidities were positively associated with rate of fatigue reduction (p = .04), (b) longer duration since COVID-19 illness was positively associated with rates of memory improvement (p = .02), (c) older age, male sex, and more comorbidities were positively associated with rate of improvement in reaction time (ps &lt; .05), and (d) more assessments completed was positively associated with rates of improvements in working memory (ps &lt; .05). Response inhibition (12.5%), simple reaction times (16.7%), and working memory (16.7%) showed the lowest rates of improvement over time. Declines in cognition were infrequent, with 4.2 - 8.3% (n = 1 to 2) declining on measures of procedural reaction time, spatial processing, inhibitory control, or working memory.Conclusions:At an average of &gt;9 months following acute COVID-19 illness, we observed longitudinal improvements in cognitive fatigue as well as processing speed, memory, and spatial reasoning. Consistent predictors of recovery were not identified, although age, sex, comorbid conditions, and time since illness predicted rates of improvement in select domains. Further analyses with a larger sample size and more stringent analyses are needed to confirm and extend these findings.

Acute Macular Neuroretinopathy after Coronavirus Disease 2019 Infection: Clinical Characteristics and Associated Factors

Objective or PurposeAcute macular neuroretinopathy (AMN) is a rare, poorly understood retinal disease that affects the outer retina. Recent studies reported the onset of AMN is associated with COVID-19 infection. However, it still lacks thorough evaluation regarding the clinical features of AMN after COVID-19 infection. DesignRetrospective cohort study. ParticipantsThis study involved online registration of patients who were diagnosed with AMN after rapid antigen or PCR tests confirmed COVID-19 infections from December 2022 to March 2023. MethodsWe interviewed all patients and completed an evaluation survey that recorded age, sex, menstruation pattern, medical history, doses of COVID-19 vaccination, symptom onset (days after fever onset), symptoms, and treatment measures. The association between clinical characteristics and baseline visual acuity was investigated. Main Outcome MeasuresDemographic and clinical characteristics of AMN after COVID-19 infection. ResultsA total of 116 eyes from 66 patients were included in the present study. The average age was 30.4 ± 6.7, and 81.8% of patients were female. The average time of ocular symptom onset was 2.62 ± 1.88 days after fever onset. Scotomas (87.9%) were the most common symptoms reported by patients, whereas 25.9% and 1.7% of eyes had blurry vision and photopsia. 80.2%, 60.3%, 26.7%, 10.3%, and 3.4% of eyes showed ellipsoid zone (EZ) disruption, hyper-reflectivity of outer nuclear layer (ONL), hyper-reflectivity of Henle layer, hyper-reflectivity of outer plexiform layer (OPL), and macular edema, respectively. A history of smoking (Coef. =0.12, 95%CI: [0.00, 0.24]), macular edema (Coef. =0.14, 95%CI: [0.00, 0.88]), hyper-reflectivity of OPL (Coef. =0.16, 95%CI: [0.08, 0.24]), hyper-reflectivity of Henle layer (Coef. =0.08, 95%CI: [0.03, 0.14]), and EZ disruption (Coef. =0.07, 95%CI: [0.00, 0.13]) were associated with worse LogMAR visual acuity at baseline. Conclusions and RelevanceAMN after COVID-19 infection is more common in young females. Hyper-reflectivity of ONL and EZ disruption are the most common OCT features of AMN. Macular edema, hyper-reflectivity of OPL, hyper-reflectivity of the Henle layer, EZ disruption, and a history of smoking are associated with worse visual acuity at baseline.

Mental health up to 12 months following SARS-CoV-2 infection: A prospective cohort study

ObjectiveTo investigate to what extent individuals report clinically relevant levels of depression, anxiety, post-traumatic stress disorder (PTSD) symptoms and concentration problems up to 12 months following COVID-19 symptom onset, using validated questionnaires. MethodsRECoVERED, a prospective cohort study in Amsterdam, the Netherlands, enrolled both hospitalized and community-dwelling adult participants diagnosed with SARS-CoV-2. Symptoms of depression and anxiety were assessed with the Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 1, 3, 6 and 12 months following illness onset. The DSM-V PTSD checklist was administered at month 3 and 9. Concentration problems were assessed using the Checklist Individual Strength concentration subscale at month 1 and 12. Generalized Estimating Equations were used to determine factors related with clinically relevant levels of depression-, anxiety- and PTSD-symptoms and concentration problems over time. ResultsIn 303 individuals, the prevalence of clinically relevant symptoms of depression, anxiety and concentration problems was 10.6% (95%CI = 7.2–15.4), 7.0% (95%CI = 4.4–11.2) and 33.6% (95%CI = 27.7–40.1), respectively, twelve months after infection. Nine months after illness onset, 4.2% (95%CI = 2.3–7.7) scored within the clinical range of PTSD. Risk factors for an increased likelihood of reporting mental health problems during follow up included initial severe/critical COVID-19, non-Dutch origin, psychological problems prior to COVID-19 and being infected during the first COVID-19 wave. ConclusionOur findings highlight that a minority of patients with COVID-19 face clinically relevant symptoms of depression, anxiety or PTSD up to 12 months after infection. The prevalence of concentration problems was high. This study contributes to the identification of specific groups for which support after initial illness is indicated.