Impact of age and comorbidities on SARS-CoV-2 vaccine-induced T cell immunity.

BACKGROUND: Older age and chronic disease are important risk factors for developing severe COVID-19. At population level, vaccine-induced immunity substantially reduces the risk of severe COVID-19 disease and hospitalization. However, the relative impact of humoral and cellular immunity on protection from breakthrough infection and severe disease is not fully understood. METHODS: In a study cohort of 655 primarily older study participants (median of 63 years (IQR: 51-72)), we determined serum levels of Spike IgG antibodies using a Multiantigen Serological Assay and quantified the frequency of SARS-CoV-2 Spike-specific CD4 + and CD8 + T cells using activation induced marker assay. This enabled characterization of suboptimal vaccine-induced cellular immunity. The risk factors of being a cellular hypo responder were assessed using logistic regression. Further follow-up of study participants allowed for an evaluation of the impact of T cell immunity on breakthrough infections. RESULTS: We show reduced serological immunity and frequency of CD4 + Spike-specific T cells in the oldest age group (≥75 years) and higher Charlson Comorbidity Index (CCI) categories. Male sex, age group ≥75 years, and CCI > 0 is associated with an increased likelihood of being a cellular hypo-responder while vaccine type is a significant risk factor. Assessing breakthrough infections, no protective effect of T cell immunity is identified. CONCLUSIONS: SARS-CoV-2 Spike-specific immune responses in both the cellular and serological compartment of the adaptive immune system increase with each vaccine dose and are progressively lower with older age and higher prevalence of comorbidities. The findings contribute to the understanding of the vaccine response in individuals with increased risk of severe COVID-19 disease and hospitalization.

Vaccination has proven very effective in protecting against severe disease and hospitalization of people with COVID-19, the disease caused by SARS-CoV-2. It is still unclear, however, how the different components of the immune system respond to SARS-CoV-2 vaccination and protect from infection and severe disease. Two of the most predominant components of the immune system are specialized proteins and cells. The proteins circulate in the blood and help clear the virus by binding to it, while the cells either kill the virus or help other cells to produce more antibodies. Here, we examined the response of these two components to the SARS-CoV-2 vaccine in 655 Danish citizens. The response of both components was lower in people over 75 years old and with other diseases. These findings help in understanding the immune responses following SARS-CoV-2 vaccination in people at increased risk of severe symptoms of COVID-19.

Cohort Profile:The Danish National Cohort Study of Effectiveness and Safety of SARS-CoV-2 vaccines (ENFORCE).

PURPOSE: The ENFORCE cohort is a national Danish prospective cohort of adults who received a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine as part of the Danish National SARS-CoV-2 vaccination programme. It was designed to investigate the long-term effectiveness, safety and durability of SARS-CoV-2 vaccines used in Denmark. PARTICIPANTS: A total of 6943 adults scheduled to receive a SARS-CoV-2 vaccine in the Danish COVID-19 vaccination programme were enrolled in the study prior to their first vaccination. Participants will be followed for a total of 2 years with five predetermined follow-up visits and additional visits in relation to any booster vaccination. Serology measurements are performed after each study visit. T-cell immunity is evaluated at each study visit for a subgroup of 699 participants. Safety information is collected from participants at visits following each vaccination. Data on hospital admissions, diagnoses, deaths and SARS-CoV-2 PCR results are collected from national registries throughout the study period. The median age of participants was 64 years (IQR 53-75), 56.6% were women and 23% were individuals with an increased risk of a serious course of COVID-19. A total of 340 (4.9%) participants tested positive for SARS-CoV-2 spike IgG at baseline. FINDINGS TO DATE: Results have been published on risk factors for humoral hyporesponsiveness and non-durable response to SARS-CoV-2 vaccination, the risk of breakthrough infections at different levels of SARS-CoV-2 spike IgG by viral variant and on the antibody neutralising capacity against different SARS-CoV-2 variants following primary and booster vaccinations. FUTURE PLANS: The ENFORCE cohort will continuously generate studies investigating immunological response, effectiveness, safety and durability of the SARS-CoV-2 vaccines. TRIAL REGISTRATION NUMBER: NCT04760132.

A Cross-Sectional Study of SARS-CoV-2 Antibodies and Risk Factors for Seropositivity in Staff in Day Care Facilities and Preschools in Denmark.

The aim of this study was to provide information about immunity against COVID-19 along with risk factors and behavior among employees in day care facilities and preschools (DCS) in Denmark. In collaboration with the Danish Union of Pedagogues, during February and March 2021, 47,810 members were offered a point-of-care rapid SARS-CoV-2 antibody test (POCT) at work and were invited to fill in an electronic questionnaire covering COVID-19 exposure. Seroprevalence data from Danish blood donors (total Ig enzyme-linked immunosorbent assay [ELISA]) were used as a proxy for the Danish population. A total of 21,018 (45%) DCS employees completed the questionnaire and reported their POCT result {median age, 44.3 years (interquartile range [IQR], [32.7 to 53.6]); females, 84.1%}, of which 20,267 (96.4%) were unvaccinated and included in analysis. A total of 1,857 (9.2%) participants tested seropositive, significantly higher than a seroprevalence at 7.6% (risk ratio [RR], 1.2; 95% confidence interval [CI], 1.14 to 1.27) among 40,541 healthy blood donors (median age, 42 years [IQR, 28 to 53]; males, 51.3%). Exposure at work (RR, 2.9; 95% CI, 2.3 to 3.6) was less of a risk factor than exposure within the household (RR, 12.7; 95% CI, 10.2 to 15.8). Less than 25% of participants reported wearing face protection at work. Most of the participants expressed some degree of fear of contracting COVID-19 both at work and outside work. SARS-CoV-2 seroprevalence was slightly higher in DCS staff than in blood donors, but possible exposure at home was associated with a higher risk than at work. DCS staff expressed fear of contracting COVID-19, though there was limited use of face protection at work. IMPORTANCE Identifying at-risk groups and evaluating preventive interventions in at-risk groups is imperative for the ongoing pandemic as well as for the control of future epidemics. Although DCS staff have a much higher risk of being infected within their own household than at their workplace, most are fearful of being infected with COVID-19 or bringing COVID-19 to work. This represents an interesting dilemma and an important issue which should be addressed by public health authorities for risk communication and pandemic planning. This study design can be used in a strategy for ongoing surveillance of COVID-19 immunity or other infections in the population. The findings of this study can be used to assess the need for future preventive interventions in DCS, such as the use of personal protective equipment.

High-dose coenzyme Q10 therapy versus placebo in patients with post COVID-19 condition: A randomized, phase 2, crossover trial.

Background: Post COVID-19 condition (PCC) is defined as symptoms lasting more than 12 weeks after developing COVID-19. Evidence of mitochondrial dysfunction has been reported in peripheral blood mononuclear cells obtained from patients with COVID-19. We hypothesized that PCC is caused by prolonged mitochondrial dysfunction. Given that coenzyme Q10 (CoQ10) can improve mitochondrial function, we examined whether high-dose CoQ10 can reduce the number and/or severity of PCC-related symptoms. Methods: In this placebo-controlled, double-blind, 2 × 2 crossover interventional trial, participants were recruited from two centres at Aarhus University Hospital and Gødstrup Hospital, Denmark. They were randomly assigned to receive either oral capsules of CoQ10 in a dose of 500 mg/day or placebo for 6 weeks, with crossover treatment after a 4-week washout period. The ED-5Q and a PCC-symptom specific questionnaire were completed by the participants at 5 visits during the 20-week study period. The primary endpoint was the change in the number and/or severity of PCC-related symptoms after the 6-week intervention compared to placebo. Participants who completed the two-dosing period were included in the primary analysis, while all participants receiving one dose were included in safety assessment. Findings: From May 25th, 2021, to September 22nd, 2021, 121 participants underwent randomization, and 119 completed both dosing periods - 59 and 60 in group A and B, respectively. At baseline, the mean PCC-related symptom score was 43.06 (95% CI: 40.18; 45.94), and the mean EQ-5D health index was 0.66 (95% CI: 0.64; 0.68). The difference between CoQ10 and placebo was not significant with respect to either the change in EQ-5D health index (with a mean difference of 0.01; 95% CI: -0.02; 0.04; p = 0.45) or the change in PCC-related symptom score (with a mean difference of -1.18; 95% CI: -3.54; 1.17; p = 0.32). Interpretation: Based on self-reported data, CoQ10 treatment does not appear to significantly reduce the number or severity of PCC-related symptoms when compared to placebo. However, we observed a significant spontaneous improvement on both scores regardless of treatment during 20 weeks observation. Funding: Placebo and CoQ10 capsules were provided by Pharma Nord, and the trial was supported by grants from the Novo Nordisk Foundation (NNF21OC0066984). This trial is registered with EudraCT, 2020-005961-16 and ClinicalTrials.gov, NCT04960215. The trial is completed.

Myopathy as a cause of Long COVID fatigue: Evidence from quantitative and single fiber EMG and muscle histopathology.

OBJECTIVE: To describe neurophysiological abnormalities in Long COVID and correlate quantitative electromyography (qEMG) and single fiber EMG (sfEMG) results to clinical scores and histopathology. METHODS: 84 patients with non-improving musculoskeletal Long COVID symptoms were examined with qEMG and sfEMG. Muscle biopsies were taken in a subgroup. RESULTS: Mean motor unit potential (MUP) duration was decreased in ≥ 1 muscles in 52 % of the patients. Mean jitter was increased in 17 % of the patients in tibialis anterior and 25 % in extensor digitorum communis. Increased jitter was seen with or without myopathic qEMG. Low quality of life score correlated with higher jitter values but not with qEMG measures. In addition to our previously published mitochondrial changes, inflammation, and capillary injury, we show now in muscle biopsies damage of terminal nerves and motor endplate with abundant basal lamina material. At the endplate, axons were present but no vesicle containing terminals. The post-synaptic cleft in areas appeared atrophic with short clefts and coarse crests. CONCLUSIONS: Myopathic changes are common in Long COVID. sfEMG abnormality is less common but may correlate with clinical scores. sfEMG changes may be due to motor endplate pathology. SIGNIFICANCE: These findings may indicate a muscle pathophysiology behind fatigue in Long COVID.

Persistent Symptoms and Sequelae After Severe Acute Respiratory Syndrome Coronavirus 2 Infection Not Requiring Hospitalization: Results From Testing Denmark, a Danish Cross-sectional Survey.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with persistent symptoms ("long COVID"). We assessed the burden of long COVID among nonhospitalized adults with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection. Methods: In the fall of 2020, a cross-sectional survey was performed in the adult Danish general population. This included a self-administered point-of-care test for SARS-CoV-2 antibodies, the Short Form Health Survey (SF-12), and coronavirus disease 2019 (COVID-19)-associated symptom questions. Nonhospitalized respondents with a positive SARS-CoV-2 PCR test ≥12 weeks before the survey (cases) were matched (1:10) to seronegative controls on age, sex, and body mass index. Propensity score-weighted odds ratios (ORs) and ORs for risk factors were estimated for each health outcome. Results: In total, 742 cases and 7420 controls were included. The attributable risk of at least 1 long-COVID symptom was 25.0 per 100 cases (95% confidence interval [CI], 22.2-27.4). Compared to controls, cases reported worse general health (OR, 5.9 [95% CI, 5.0-7.0]) and had higher odds for a broad range of symptoms, particularly loss of taste (OR, 11.8 [95% CI, 9.5-14.6]) and smell (OR, 11.2 [95% CI, 9.1-13.9]). Physical and Mental Component Summary scores were also significantly reduced with differences of -2.5 (95% CI, -3.1 to -1.8) and -2.0 (95% CI, -2.7 to -1.2), respectively. Female sex and severity of initial infection were major risk factors for long COVID. Conclusions: Nonhospitalized SARS-CoV-2 PCR-positive individuals had significantly reduced physical and mental health, and 1 in 4 reported persistence of at least 1 long-COVID symptom.

Characteristics of a Danish Post-COVID Cohort Referred for Examination due to Persistent Symptoms Six Months after Mild Acute COVID-19.

BACKGROUND: Post-COVID Clinics were recommended for patients with persistent symptoms following COVID-19, but no specific tests were suggested for evaluation. This study aimed to present a post-COVID clinic patient cohort and evaluate the use of a post-COVID symptom questionnaire (PCQ) score. METHODS: Patients were referred from a population of approximately 1 million citizens. PCQ and standardized health scales were registered. Descriptive analyses were performed to assess the prevalence of symptoms, and correlation analyses was undertaken to asses convergent and discriminant trends between PCQ scores and health scales. RESULTS: Of 547 patients, 447 accepted inclusion. The median age was 47 years and 12% of the patients were hospitalized. At a median of 6.3 (IQR 4.4-9.9) months after the onset of symptoms, 82% of the patients reported both physical exhaustion and concentration difficulties. Functional disability and extreme fatigue were reported as moderate to severe by 33% and 62% of the patients, respectively. The PCQ score correlated significantly with each of the standardized health scales. CONCLUSION: Patients referred to a Post-COVID Clinic were previously generally healthy. At the time of diagnosis, they reported multiple symptoms with severely affected health. The PCQ score could be used as valid measure of Post-COVID severity.

Self-Reported Long COVID and Its Association with the Presence of SARS-CoV-2 Antibodies in a Danish Cohort up to 12 Months after Infection.

The majority of long coronavirus disease (COVID) symptoms are not specific to COVID-19 and could be explained by other conditions. The present study aimed to explore whether Danish individuals with a perception that they suffer from long COVID have antibodies against the nucleocapsid antigen, as a proxy for detecting previous infection. The study was conducted in February and March 2021, right after the second surge of the COVID-19 pandemic in Denmark. All members of the social media group on Facebook "Covidramte med senfølger" ("long COVID sufferers'') above the age of 17 years and living in Denmark were invited to participate in a short electronic questionnaire about long COVID risk factors and symptoms. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein was detected in blood samples as a proxy for natural SARS-CoV-2 infection. The final study population comprised 341 participants (90.6% females) who completed blood sampling and answered the questionnaire. A total of 232 (68%) were seropositive (median age, 49.5 years; interquartile range [IQR], 41 to 55 years; 90.1% females). There was no significant difference between sexes and serostatus. Seronegative and seropositive individuals had a similar burden of symptoms that could be attributed to long COVID. Time since perceived COVID-19 was significantly longer in the group of seronegative individuals than the seropositive ones (P < 0.001). This study suggests that long-COVID sufferers are mostly women and showed that a third of the participants did not have detectable anti-N-protein antibodies. It emphasizes the importance of early confirmation of COVID-19, as this study indicates an overlap between long-COVID symptoms and symptoms that are possibly of another origin. IMPORTANCE This cohort study included questionnaire data as well as anti-nucleocapsid antibody analysis, allowing us to determine whether participants were seropositive due to vaccination or natural infection. The study emphasizes the importance of early confirmation of COVID-19, as antibodies recede with time, and it indicates an overlap between long COVID symptoms and symptoms possibly of another origin.

Comparison of vaccine-induced antibody neutralization against SARS-CoV-2 variants of concern following primary and booster doses of COVID-19 vaccines.

The SARS-CoV-2 pandemic has, as of July 2022, infected more than 550 million people and caused over 6 million deaths across the world. COVID-19 vaccines were quickly developed to protect against severe disease, hospitalization and death. In the present study, we performed a direct comparative analysis of four COVID-19 vaccines: BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna), ChAdOx1 (Oxford/AstraZeneca) and Ad26.COV2.S (Johnson & Johnson/Janssen), following primary and booster vaccination. We focused on the vaccine-induced antibody-mediated immune response against multiple SARS-CoV-2 variants: wildtype, B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta) and B.1.1.529 (Omicron). The analysis included the quantification of total IgG levels against SARS-CoV-2 Spike, as well as the quantification of antibody neutralization titers. Furthermore, the study assessed the high-throughput ACE2 competition assay as a surrogate for the traditional pseudovirus neutralization assay. The results demonstrated marked differences in antibody-mediated immune responses. The lowest Spike-specific IgG levels and antibody neutralization titers were induced by one dose of the Ad26.COV2.S vaccine, intermediate levels by two doses of the BNT162b2 vaccine, and the highest levels by two doses of the mRNA-1273 vaccine or heterologous vaccination of one dose of the ChAdOx1 vaccine and a subsequent mRNA vaccine. The study also demonstrated that accumulation of SARS-CoV-2 Spike protein mutations was accompanied by a marked decline in antibody neutralization capacity, especially for B.1.1.529. Administration of a booster dose was shown to significantly increase Spike-specific IgG levels and antibody neutralization titers, erasing the differences between the vaccine-induced antibody-mediated immune response between the four vaccines. The findings of this study highlight the importance of booster vaccines and the potential inclusion of future heterologous vaccination strategies for broad protection against current and emerging SARS-CoV-2 variants.

A randomized placebo-controlled trial of convalescent plasma for adults hospitalized with COVID-19 pneumonia.

Passive immunotherapy with convalescent plasma may be the only available agent during the early phases of a pandemic. Here, we report safety and efficacy of high-titer convalescent plasma for COVID-19 pneumonia. Double-blinded randomized multicenter placebo-controlled trial of adult patients hospitalized with COVID-19 pneumonia. The intervention was COVID-19 convalescent plasma and placebo was saline allocated 2:1. The primary outcome was clinical status 14 days after the intervention evaluated on a clinical ordinal scale. The trial was registered at ClinicalTrials.Gov, NCT04345289, 14/04/2020. The CCAP-2 trial was terminated prematurely due to futility. Of 147 patients randomized, we included 144 patients in the modified intention-to-treat population. The ordinal clinical status 14 days post-intervention was comparable between treatment groups (odds ratio (OR) 1.41, 95% confidence interval (CI) 0.72-2.09). Results were consistent when evaluating clinical progression on an individual level 14 days after intervention (OR 1.09; 95% CI 0.46-1.73). No significant differences in length of hospital stay, admission to ICU, frequency of severe adverse events or all-cause mortality during follow-up were found between the intervention and the placebo group. Infusion of convalescent plasma did not influence clinical progression, survival or length of hospitalization in patients with COVID-19 pneumonia.

Clinical presentation and cardiac imaging findings in patient cases of perimyocarditis and pericarditis with a temporal association to SARS-CoV-2 vaccination

Aims We aimed to investigate and present cases of perimyocarditis and pericarditis verified by cardiovascular resonance (CMR) imaging in patients with a strong temporal association to SARS-CoV-2 vaccination. We sought to describe the clinical presentation including coronary artery angiography, CMR, transthoracic echocardiography, blood samples, electrocardiography, and symptoms. Methods We included 10 patients admitted with chest pain shortly after vaccination for SARS-CoV-2, who were diagnosed with pericarditis or perimyocarditis by CMR. We reviewed the CMR, echocardiography, electrocardiography, blood samples, coronary artery angiography, vital signs and medical history. The updated Lake Louise Criteria were used to determine the diagnosis by CMR. Results Eight patients had perimyocarditis and two patients had pericarditis. The mean age was 22 ± 5 years (range 16 to 31 years), 90% were male. The median time from vaccination to hospital admission was 4 days (range 2 to 28 days). Admissions were seen after vaccination with three different SARS-CoV-2 vaccine manufacturers. Nine Patients had ST-elevation on the initial electrocardiography. Peak troponins varied from 357 to 23,547 ng/l, with a median of 4,304 ng/l. Two patients had an LVEF <50% on echocardiography and four patients had left ventricular global longitudinal strain values <18%. CMR revealed preserved left ventricular ejection fraction (LVEF), although one patient had decreased LVEF on CMR. The T1 and T2 mapping values were increased in all patients. Of the 8 patients with perimyocarditis, all patients had signs of myocardial injury in the lateral segments of the left ventricle. Conclusions This case series of 10 patients supports the emerging evidence of an association between vaccination for SARS-CoV-2 and perimyocarditis and pericarditis, especially in young males. The temporal association was seen after vaccines from three different manufacturers. Imaging data from echocardiography and CMR displayed normal to mildly impaired cardiac function, usually with a mild disease course.

Levels of SARS-CoV-2 antibodies among fully vaccinated individuals with Delta or Omicron variant breakthrough infections.

SARS-CoV-2 variants of concern have continuously evolved and may erode vaccine induced immunity. In this observational cohort study, we determine the risk of breakthrough infection in a fully vaccinated cohort. SARS-CoV-2 anti-spike IgG levels were measured before first SARS-CoV-2 vaccination and at day 21-28, 90 and 180, as well as after booster vaccination. Breakthrough infections were captured through the Danish National Microbiology database. incidence rate ratio (IRR) for breakthrough infection at time-updated anti-spike IgG levels was determined using Poisson regression. Among 6076 participants, 127 and 364 breakthrough infections due to Delta and Omicron variants were observed. IRR was 0.29 (95% CI 0.15-0.56) for breakthrough infection with the Delta variant, comparing the highest and lowest quintiles of anti-spike IgG. For Omicron, no significant differences in IRR were observed. These results suggest that quantitative level of anti-spike IgG have limited impact on the risk of breakthrough infection with Omicron.

Cardiac Performance and Cardiopulmonary Fitness After Infection With SARS-CoV-2.

Aims: Persistent cardiac symptoms are an increasingly reported phenomenon following COVID-19. However, the underlying cause of cardiac symptoms is unknown. This study aimed to identify the underlying causes, if any, of these symptoms 1 year following acute COVID-19 infection. Methods and Results: 22 individuals with persistent cardiac symptoms were prospectively investigated using echocardiography, cardiovascular magnetic resonance (CMR), 6-min walking test, cardio-pulmonary exercise testing and electrocardiography. A median of 382 days (IQR 368, 442) passed between diagnosis of COVID-19 and investigation. As a cohort their echocardiography, CMR, 6-min walking test and exercise testing results were within the normal ranges. There were no differences in left ventricular ejection fraction (61.45 ± 6.59 %), global longitudinal strain (19.80 ± 3.12 %) or tricuspid annular plane systolic excursion (24.96 ± 5.55 mm) as measured by echocardiography compared to a healthy control group. VO2 max (2045.00 ± 658.40 ml/min), % expected VO2 max (114.80 ± 23.08 %) and 6-minute distance walked (608.90 ± 54.51 m) exceeded that expected for the patient cohort, whilst Troponin I (5.59 ± 6.59 ng/l) and Nt-proBNP (88.18 ± 54.27 ng/l) were normal. Conclusion: Among a cohort of 22 patients with self-reported persistent cardiac symptoms, we identified no underlying cardiac disease or reduced cardiopulmonary fitness 1 year following COVID-19.

SARS-CoV-2 antibody prevalence among homeless people and shelter workers in Denmark: a nationwide cross-sectional study.

BACKGROUND: People experiencing homelessness (PEH) and associated shelter workers may be at higher risk of infection with "Severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2). The aim of this study was to determine the prevalence of SARS-CoV-2 among PEH and shelter workers in Denmark. DESIGN AND METHODS: In November 2020, we conducted a nationwide cross-sectional seroprevalence study among PEH and shelter workers at 21 recruitment sites in Denmark. The assessment included a point-of-care test for antibodies against SARS-CoV-2, followed by a questionnaire. The seroprevalence was compared to that of geographically matched blood donors considered as a proxy for the background population, tested using a total Ig ELISA assay. RESULTS: We included 827 participants in the study, of whom 819 provided their SARS-CoV-2 antibody results. Of those, 628 were PEH (median age 50.8 (IQR 40.9-59.1) years, 35.5% female) and 191 were shelter workers (median age 46.6 (IQR 36.1-55.0) years and 74.5% female). The overall seroprevalence was 6.7% and was similar among PEH and shelter workers (6.8% vs 6.3%, p = 0.87); and 12.2% among all participants who engaged in sex work. The overall participant seroprevalence was significantly higher than that of the background population (2.9%, p < 0.001). When combining all participants who reported sex work or were recruited at designated safe havens, we found a significantly increased risk of seropositivity compared to other participants (OR 2.23, 95%CI 1.06-4.43, p = 0.02). Seropositive and seronegative participants reported a similar presence of at least one SARS-CoV-2 associated symptom (49% and 54%, respectively). INTERPRETATIONS: The prevalence of SARS-CoV-2 antibodies was more than twice as high among PEH and associated shelter workers, compared to the background population. These results could be taken into consideration when deciding in which phase PEH are eligible for a vaccine, as part of the Danish national SARS-CoV-2 vaccination program rollout. FUNDING: TrygFonden and HelseFonden.

Myopathy as a cause of fatigue in long-term post-COVID-19 symptoms: Evidence of skeletal muscle histopathology.

BACKGROUND AND PURPOSE: Among post-COVID-19 symptoms, fatigue is reported as one of the most common, even after mild acute infection, and as the cause of fatigue, myopathy diagnosed by electromyography has been proposed in previous reports. This study aimed to explore the histopathological changes in patients with post-COVID-19 fatigue. METHODS: Sixteen patients (mean age = 46 years) with post-COVID-19 complaints of fatigue, myalgia, or weakness persisting for up to 14 months were included. In all patients, quantitative electromyography and muscle biopsies analyzed with light and electron microscopy were taken. RESULTS: Muscle weakness was present in 50% and myopathic electromyography in 75%, and in all patients there were histological changes. Muscle fiber atrophy was found in 38%, and 56% showed indications of fiber regeneration. Mitochondrial changes, comprising loss of cytochrome c oxidase activity, subsarcollemmal accumulation, and/or abnormal cristae, were present in 62%. Inflammation was found in 62%, seen as T lymphocytes and/or muscle fiber human leukocyte antigen ABC expression. In 75%, capillaries were affected, involving basal lamina and cells. In two patients, uncommon amounts of basal lamina were found, not only surrounding muscle fibers but also around nerves and capillaries. CONCLUSIONS: The wide variety of histological changes in this study suggests that skeletal muscles may be a major target of SARS-CoV-2, causing muscular post-COVID-19 symptoms. The mitochondrial changes, inflammation, and capillary injury in muscle biopsies can cause fatigue in part due to reduced energy supply. Because most patients had mild-moderate acute affection, the new variants that might cause less severe acute disease could still have the ability to cause long-term myopathy.

Responses to a Neutralizing Monoclonal Antibody for Hospitalized Patients With COVID-19 According to Baseline Antibody and Antigen Levels : A Randomized Controlled Trial.

BACKGROUND: In a randomized, placebo-controlled, clinical trial, bamlanivimab, a SARS-CoV-2-neutralizing monoclonal antibody, given in combination with remdesivir, did not improve outcomes among hospitalized patients with COVID-19 based on an early futility assessment. OBJECTIVE: To evaluate the a priori hypothesis that bamlanivimab has greater benefit in patients without detectable levels of endogenous neutralizing antibody (nAb) at study entry than in those with antibodies, especially if viral levels are high. DESIGN: Randomized, placebo-controlled trial. (ClinicalTrials.gov: NCT04501978). SETTING: Multicenter trial. PATIENTS: Hospitalized patients with COVID-19 without end-organ failure. INTERVENTION: Bamlanivimab (7000 mg) or placebo. MEASUREMENTS: Antibody, antigen, and viral RNA levels were centrally measured on stored specimens collected at baseline. Patients were followed for 90 days for sustained recovery (defined as discharge to home and remaining home for 14 consecutive days) and a composite safety outcome (death, serious adverse events, organ failure, or serious infections). RESULTS: Among 314 participants (163 receiving bamlanivimab and 151 placebo), the median time to sustained recovery was 19 days and did not differ between the bamlanivimab and placebo groups (subhazard ratio [sHR], 0.99 [95% CI, 0.79 to 1.22]; sHR > 1 favors bamlanivimab). At entry, 50% evidenced production of anti-spike nAbs; 50% had SARS-CoV-2 nucleocapsid plasma antigen levels of at least 1000 ng/L. Among those without and with nAbs at study entry, the sHRs were 1.24 (CI, 0.90 to 1.70) and 0.74 (CI, 0.54 to 1.00), respectively (nominal P for interaction = 0.018). The sHR (bamlanivimab vs. placebo) was also more than 1 for those with plasma antigen or nasal viral RNA levels above median level at entry and was greatest for those without antibodies and with elevated levels of antigen (sHR, 1.48 [CI, 0.99 to 2.23]) or viral RNA (sHR, 1.89 [CI, 1.23 to 2.91]). Hazard ratios for the composite safety outcome (<1 favors bamlanivimab) also differed by serostatus at entry: 0.67 (CI, 0.37 to 1.20) for those without and 1.79 (CI, 0.92 to 3.48) for those with nAbs. LIMITATION: Subgroup analysis of a trial prematurely stopped because of futility; small sample size; multiple subgroups analyzed. CONCLUSION: Efficacy and safety of bamlanivimab may differ depending on whether an endogenous nAb response has been mounted. The limited sample size of the study does not allow firm conclusions based on these findings, and further independent trials are required that assess other types of passive immune therapies in the same patient setting. PRIMARY FUNDING SOURCE: U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.

Characteristics associated with serological COVID-19 vaccine response and durability in an older population with significant comorbidity: the Danish Nationwide ENFORCE Study.

OBJECTIVES: To identify individual characteristics associated with serological COVID-19 vaccine responsiveness and the durability of vaccine-induced antibodies. METHODS: Adults without history of SARS-CoV-2 infection from the Danish population scheduled for SARS-CoV-2 vaccination were enrolled in this parallel group, phase 4 study. SARS-CoV-2 Spike IgG and Spike-ACE2-receptor-blocking antibodies were measured at days 0, 21, 90, and 180. Vaccine responsiveness was categorized according to Spike IgG and Spike-ACE2-receptor-blocking levels at day 90 after first vaccination. Nondurable vaccine response was defined as day-90 responders who no longer had significant responses by day 180. RESULTS: Of 6544 participants completing two vaccine doses (median age 64 years; interquartile range: 54-75), 3654 (55.8%) received BTN162b2, 2472 (37.8%) mRNA-1273, and 418 (6.4%) ChAdOx1 followed by an mRNA vaccine. Levels of both types of antibodies increased from baseline to day 90 and then decreased to day 180. The decrease was more pronounced for levels of Spike-ACE2-receptor-blocking antibodies than for Spike IgG. Proportions with vaccine hyporesponsiveness and lack of durable response were 5.0% and 12.1% for Spike IgG and 12.7% and 39.6% for Spike-ACE2-receptor-blocking antibody levels, respectively. Male sex, vaccine type, and number of comorbidities were associated with all four outcomes. Additionally, age ≥75 years was associated with hyporesponsiveness for Spike-ACE2-receptor-blocking antibodies (adjusted odds ratio: 1.59; 95% confidence interval: 1.25-2.01) but not for Spike IgG. DISCUSSION: Comorbidity, male sex, and vaccine type were risk factors for hyporesponsiveness and nondurable response to COVID-19 vaccination. The functional activity of vaccine-induced antibodies declined with increasing age and had waned to pre-second-vaccination levels for most individuals after 6 months.

Seroprevalence of SARS-CoV-2 antibodies in social housing areas in Denmark.

BACKGROUND: COVID-19 is thought to be more prevalent among ethnic minorities and individuals with low socioeconomic status. We aimed to investigate the prevalence of SARS-CoV-2 antibodies during the COVID-19 pandemic among citizens 15 years or older in Denmark living in social housing (SH) areas. METHODS: We conducted a study between January 8th and January 31st, 2021 with recruitment in 13 selected SH areas. Participants were offered a point-of-care rapid SARS-CoV-2 IgM and IgG antibody test and a questionnaire concerning risk factors associated with COVID-19. As a proxy for the general Danish population we accessed data on seroprevalence from Danish blood donors (total Ig ELISA assay) in same time period. RESULTS: Of the 13,279 included participants, 2296 (17.3%) were seropositive (mean age 46.6 (SD 16.4) years, 54.2% female), which was 3 times higher than in the general Danish population (mean age 41.7 (SD 14.1) years, 48.5% female) in the same period (5.8%, risk ratios (RR) 2.96, 95% CI 2.78-3.16, p > 0.001). Seropositivity was higher among males (RR 1.1, 95% CI 1.05-1.22%, p = 0.001) and increased with age, with an OR seropositivity of 1.03 for each 10-year increase in age (95% CI 1.00-1.06, p = 0.031). Close contact with COVID-19-infected individuals was associated with a higher risk of infection, especially among household members (OR 5.0, 95% CI 4.1-6.2 p < 0,001). Living at least four people in a household significantly increased the OR of seropositivity (OR 1.3, 95% CI 1.0-1.6, p = 0.02) as did living in a multi-generational household (OR 1.3 per generation, 95% CI 1.1-1.6, p = 0.003). Only 1.6% of participants reported not following any of the national COVID-19 recommendations. CONCLUSIONS: Danish citizens living in SH areas of low socioeconomic status had a three times higher SARS-CoV-2 seroprevalence compared to the general Danish population. The seroprevalence was significantly higher in males and increased slightly with age. Living in multiple generations households or in households of more than four persons was a strong risk factor for being seropositive. Results of this study can be used for future consideration of the need for preventive measures in the populations living in SH areas.