June 15, 2023

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Clinical Reports

Anemia as a risk factor for disease progression in patients admitted for COVID-19
- In respiratory infections, anemia is both a consequence of acute inflammation and a predictor of poor clinical outcomes. There are few studies investigating the role of anemia in COVID-19, suggesting a potential role in predicting disease severity. In this study, researchers aimed to assess the association between the presence of anemia at admission and incidence of severe disease and death in patients hospitalized for COVID-19. Among the 1562 patients included in the analysis, prevalence of anemia was 45.1%. Patients with anemia were significantly older, reported more co-morbidities, and presented higher baseline levels of procalcitonin, CRP, ferritin and IL-6. Overall, the crude incidence of mortality was about four times higher in patients with anemia compared to those without. After adjusting for 17 potential confounders, the presence of anemia significantly increased the risk of death and of risk of severe COVID-19. This study provides evidence that, in patients hospitalized for COVID-19, anemia is both associated with a more pronounced baseline pro-inflammatory profile and higher incidence of in-hospital mortality and severe disease.
Impact of fatigue as the primary determinant of functional limitations among patients with post-COVID-19 syndrome
- The primary outcome was the baseline Work and Social Adjustment Scale (WSAS). WSAS measures the functional limitations of the patient; scores of ≥20 indicate moderately severe limitations. Other symptoms explored included fatigue (Functional Assessment of Chronic Illness Therapy–Fatigue), depression (Patient Health Questionnaire–Eight Item Depression Scale), anxiety (Generalised Anxiety Disorder Scale, Seven-Item), breathlessness (Medical Research Council Dyspnoea Scale and Dyspnoea-12), cognitive impairment (Perceived Deficits Questionnaire, Five-Item Version) and HRQoL (EQ-5D). Symptoms and demographic characteristics associated with more severe functional limitations were identified using logistic regression analysis. 3541 (94%) patients were of working age (18-65); mean age (SD) 48 (12) years; 1282 (71%) were female and 89% were white. 51% reported losing ≥1 days from work in the previous 4 weeks; 20% reported being unable to work at all. Mean WSAS score at baseline was 21 (SD 10) with 53% scoring ≥20. Factors associated with WSAS scores of ≥20 were high levels of fatigue, depression and cognitive impairment. Fatigue was found to be the main symptom contributing to a high WSAS score. A high proportion of this PCS treatment-seeking population was of working age with over half reporting moderately severe or worse functional limitation. There were substantial impacts on ability to work and activities of daily living in people with PCS. Clinical care and rehabilitation should address the management of fatigue as the dominant symptom explaining variation in functionality.
Post-COVID condition in patients with inflammatory rheumatic diseases
- Post-COVID condition after SARS-CoV-2 omicron infections was higher in patients with inflammatory rheumatic disease than in healthy controls based on WHO classification guidelines. However, because more patients with inflammatory rheumatic disease than healthy controls without a history of COVID-19 reported symptoms that are commonly used to define a post-COVID condition during the first 2 years of the pandemic, it is likely that the observed difference in post-COVID condition between patients and controls might in part be explained by clinical manifestations in the context of underlying rheumatic diseases. This highlights the limitations of applying current criteria for post-COVID condition in patients with inflammatory rheumatic disease, and suggests it might be appropriate for physicians to keep a nuanced attitude when communicating the long-term consequences of COVID-19.
Persistent serum protein signatures define an inflammatory subcategory of long COVID
- Long COVID or post-acute sequelae of SARS-CoV-2 (PASC) is a clinical syndrome featuring diverse symptoms that can persist for months following acute SARS-CoV-2 infection. The aetiologies may include persistent inflammation, unresolved tissue damage or delayed clearance of viral protein or RNA, but the biological differences they represent are not fully understood. Here we evaluate the serum proteome in samples, longitudinally collected from 55 PASC individuals with symptoms lasting ≥60 days after onset of acute infection, in comparison to samples from symptomatically recovered SARS-CoV-2 infected and uninfected individuals. This analysis indicates heterogeneity in PASC and identified subsets with distinct signatures of persistent inflammation. Type II interferon signaling and canonical NF-κB signaling (particularly associated with TNF), appear to be the most differentially enriched signaling pathways, distinguishing a group of patients characterized also by a persistent neutrophil activation signature. These findings help to clarify biological diversity within PASC, identify participants with molecular evidence of persistent inflammation, and highlight dominant pathways that may have diagnostic or therapeutic relevance, including a protein panel that we propose as having diagnostic utility for differentiating inflammatory and non-inflammatory PASC.
The relevance of pacing strategies in managing symptoms of post-COVID-19 syndrome
- Post-COVID-19 syndrome (PCS) shares many features with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). PCS represents a major health issue worldwide because it severely impacts patients’ work activities and their quality of life. In the absence of treatment for both conditions and given the beneficial effect of pacing strategies in ME/CFS, researchers conducted this study to assess the effectiveness of pacing in PCS patients. Researchers retrospectively included patients meeting the World Health Organization definition of PCS who attended the Internal Medicine Department of Angers University Hospital, France between June 2020 and June 2022, and were followed up until December 2022. Pacing strategies were systematically proposed for all patients. Their medical records were reviewed and data related to baseline and follow-up assessments were collected. This included epidemiological characteristics, COVID-19 symptoms and associated conditions, fatigue features, perceived health status, employment activity, and the degree of pacing adherence assessed by the engagement in pacing subscale (EPS). Recovery was defined as the ability to return to work, and improvement was regarded as the reduction of the number and severity of symptoms. A total of 86 patients were included and followed-up for a median time of 10 [6–13] months. Recovery and improvement rates were 33.7% and 23.3%, respectively. The EPS score was the only variable significantly associated with recovery on multivariate analysis (OR 40.43 [95% CI 6.22–262.6], p < 0.001). Patients who better adhered to pacing (high EPS scores) experienced significantly higher recovery and improvement rates (60–33.3% respectively) than those with low (5.5–5.5% respectively), or moderate (4.3–17.4% respectively) scores. These findings demonstrated that pacing is effective in the management of patients with PCS, and that high levels of adherence to pacing are associated with better outcomes.

Antiviral Therapeutics and Vaccines

Genetic stabilization of attenuated oral vaccines against poliovirus types 1 and 3
- Vaccination with Sabin, a live attenuated oral polio vaccine (OPV), results in robust intestinal and humoral immunity and has been key to controlling poliomyelitis. As with any RNA virus, OPV evolves rapidly to lose attenuating determinants critical to the reacquisition of virulence1,2,3 resulting in vaccine-derived, virulent poliovirus variants. Circulation of these variants within underimmunized populations leads to further evolution of circulating, vaccine-derived poliovirus with higher transmission capacity, representing a significant risk of polio re-emergence. A new type 2 OPV (nOPV2), with promising clinical data on genetic stability and immunogenicity, recently received authorization from the World Health Organization for use in response to circulating, vaccine-derived poliovirus outbreaks. Here researchers report the development of two additional live attenuated vaccine candidates against type 1 and 3 polioviruses. The candidates were generated by replacing the capsid coding region of nOPV2 with that from Sabin 1 or 3. These chimeric viruses show growth phenotypes similar to nOPV2 and immunogenicity comparable to their parental Sabin strains, but are more attenuated. These experiments in mice and deep sequencing analysis confirmed that the candidates remain attenuated and preserve all the documented nOPV2 characteristics concerning genetic stability following accelerated virus evolution. Importantly, these vaccine candidates are highly immunogenic in mice as monovalent and multivalent formulations and may contribute to poliovirus eradication.
Evaluation of Oseltamivir Used to Prevent Hospitalization in Outpatients With Influenza
- Of 2352 studies identified, 15 were included. The intention-to-treat infected (ITTi) population was comprised of 6295 individuals with 54.7% prescribed oseltamivir. Across study populations, 53.6% (5610 of 10 471) were female and the mean age was 45.3 (14.5) years. Overall, oseltamivir was not associated with reduced risk of hospitalization within the ITTi population. Oseltamivir was also not associated with reduced hospitalization in older populations or in patients considered at greater risk of hospitalization. Within the safety population, oseltamivir was associated with increased nausea and vomiting but not serious adverse events. In this systematic review and meta-analysis among influenza-infected outpatients, oseltamivir was not associated with a reduced risk of hospitalization but was associated with increased gastrointestinal adverse events. To justify continued use for this purpose, an adequately powered trial in a suitably high-risk population is justified.
Has COVID-19 Threatened Routine Childhood Vaccination? Insights From US Public Opinion Polls
- After approval of COVID-19 vaccines for adolescents ages 12–15 in 2021, only 40 percent of US adults indicated high trust in public health agencies to provide accurate information about the safety of these vaccines. Only a minority share of the public has expressed high trust in the Food and Drug Administration or the Centers for Disease Control and Prevention to provide reliable information about COVID-19 vaccines throughout the pandemic, with only 25 percent to 28 percent and 31 percent to 36 percent reporting “a great deal of trust,” respectively. In contrast, high trust in public health agencies to provide accurate information about routine childhood vaccine safety actually increased by 17 percentage points between 2019 and 2022, from 37 percent to 54 percent. In summary, these polls suggest that Americans have not grown more anti-vaccination during the COVID-19 pandemic, but rather, more anti-mandate.
Successful Treatment of Persistent Symptomatic Coronavirus Disease 19 (COVID-19) Infection with Extended Duration Nirmatrelvir/Ritonavir
- Persistent symptomatic coronavirus disease 2019 (COVID-19) is a distinct clinical entity among patients with hematologic malignancies and/or profound immunosuppression. The optimal medical management is unknown. Rsearchers describe 2 patients with symptomatic COVID-19 for almost 6 months who were successfully treated in the ambulatory setting with extended courses of nirmatrelvir/ritonavir.
Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT)
- Between Dec 30, 2020, and Jan 28, 2022, 6602 people were assessed for eligibility and 1431 were enrolled and randomly assigned. Of 1323 participants who received a dose of study treatment and were included in the modified intention-to-treat population, 1126 consented for long-term follow-up and completed at least one survey after the assessment for long COVID at day 180 (564 received metformin and 562 received matched placebo; a subset of participants in the metformin vs placebo trial were also randomly assigned to receive ivermectin or fluvoxamine). 1074 (95%) of 1126 participants completed at least 9 months of follow-up. 632 (56·1%) of 1126 participants were female and 494 (43·9%) were male; 44 (7·0%) of 632 women were pregnant. The median age was 45 years (IQR 37–54) and median BMI was 29·8 kg/m2 (IQR 27·0–34·2). Overall, 93 (8·3%) of 1126 participants reported receipt of a long COVID diagnosis by day 300. The cumulative incidence of long COVID by day 300 was 6·3% (95% CI 4·2–8·2) in participants who received metformin and 10·4% (7·8–12·9) in those who received identical metformin placebo (hazard ratio [HR] 0·59, 95% CI 0·39–0·89; p=0·012). The metformin beneficial effect was consistent across prespecified subgroups. When metformin was started within 3 days of symptom onset, the HR was 0·37 (95% CI 0·15–0·95). There was no effect on cumulative incidence of long COVID with ivermectin (HR 0·99, 95% CI 0·59–1·64) or fluvoxamine (1·36, 0·78–2·34) compared with placebo. Outpatient treatment with metformin reduced long COVID incidence by about 41%, with an absolute reduction of 4·1%, compared with placebo. Metformin has clinical benefits when used as outpatient treatment for COVID-19 and is globally available, low-cost, and safe.
Metformin reduces SARS-CoV-2 in a Phase 3 Randomized Placebo Controlled Clinical Trial
- Current antiviral treatment options for SARS-CoV-2 infections are not available globally, cannot be used with many medications, and are limited to virus-specific targets. Biophysical modeling of SARS-CoV-2 replication predicted that protein translation is an especially attractive target for antiviral therapy. Literature review identified metformin, widely known as a treatment for diabetes, as a potential suppressor of protein translation via targeting of the host mTor pathway. In vitro, metformin has antiviral activity against RNA viruses including SARS-CoV-2. In the COVID-OUT phase 3, randomized, placebo-controlled trial of outpatient treatment of COVID-19, metformin had a 42% reduction in ER visits/hospitalizations/death through 14 days; a 58% reduction in hospitalizations/death through 28 days, and a 42% reduction in Long COVID through 10 months. Here researchers show viral load analysis of specimens collected in the COVID-OUT trial that the mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (−0.56 log10 copies/mL; 95%CI, -1.05 to -0.06, p=0.027) while there was no virologic effect for ivermectin or fluvoxamine vs placebo. The metformin effect was consistent across subgroups and with emerging data. These results demonstrate, consistent with model predictions, that a safe, widely available, well-tolerated, and inexpensive oral medication, metformin, can be repurposed to significantly reduce SARS-CoV-2 viral load.

Epidemiology

To Track Progress Toward Poliomyelitis Eradication — Worldwide, 2021–2022
- The primary means for detecting poliovirus is through acute flaccid paralysis (AFP) surveillance, which is supplemented by environmental surveillance of sewage samples. During 2021–2022, among 34 priority countries experiencing or at high risk for poliovirus transmission, 26 (76.5%) met national AFP surveillance indicator targets, and the number of environmental surveillance sites increased by 31%. However, substantial national and subnational AFP surveillance gaps persist. Maintaining high-quality surveillance is critical to achieving the goal of global polio eradication. Monitoring surveillance indicators is important to identify gaps and guide surveillance-strengthening activities, particularly in countries at high risk for poliovirus circulation.
Viral emissions into the air and environment after SARS-CoV-2 human challenge: a phase 1, open label, first-in-human study
- Effectively implementing strategies to curb SARS-CoV-2 transmission requires understanding who is contagious and when. Although viral load on upper respiratory swabs has commonly been used to infer contagiousness, measuring viral emissions might be more accurate to indicate the chance of onward transmission and identify likely routes. Researchers aimed to correlate viral emissions, viral load in the upper respiratory tract, and symptoms, longitudinally, in participants who were experimentally infected with SARS-CoV-2. In this phase 1, open label, first-in-human SARS-CoV-2 experimental infection study at quarantine unit at the Royal Free London NHS Foundation Trust, London, UK, healthy adults aged 18–30 years who were unvaccinated for SARS-CoV-2, not previously known to have been infected with SARS-CoV-2, and seronegative at screening were recruited. Between March 6 and July 8, 2021, 36 participants (ten female and 26 male) were recruited and 18 (53%) of 34 participants became infected, resulting in protracted high viral loads in the nose and throat following a short incubation period, with mild-to-moderate symptoms. Two participants were excluded from the per-protocol analysis owing to seroconversion between screening and inoculation, identified post hoc. Viral RNA was detected in 63 (25%) of 252 Coriolis air samples from 16 participants, 109 (43%) of 252 mask samples from 17 participants, 67 (27%) of 252 hand swabs from 16 participants, and 371 (29%) of 1260 surface swabs from 18 participants. Viable SARS-CoV-2 was collected from breath captured in 16 masks and from 13 surfaces, including four small frequently touched surfaces and nine larger surfaces where airborne virus could deposit. Viral emissions correlated more strongly with viral load in nasal swabs than throat swabs. Two individuals emitted 86% of airborne virus, and the majority of airborne virus collected was released on 3 days. Individuals who reported the highest total symptom scores were not those who emitted most virus. Very few emissions occurred before the first reported symptom (7%) and hardly any before the first positive lateral flow antigen test (2%). Interpretation After controlled experimental inoculation, the timing, extent, and routes of viral emissions was heterogeneous. Researchers observed that a minority of participants were high airborne virus emitters, giving support to the notion of superspreading individuals or events. This data implicates the nose as the most important source of emissions. Frequent self-testing coupled with isolation upon awareness of first symptoms could reduce onward transmissions.