Effect of Vitamin D in Long COVID Patients.

Vitamin D deficiency has been studied in the context of acute coronavirus disease 2019 (COVID-19), revealing associations with increased severity and mortality. Yet, the influence of vitamin D on long COVID symptoms remains unknown. The purpose of this study is to examine the effect of vitamin D on long COVID symptoms. Over the study period, 50,432 individuals within the catchment area of the outpatient COVID-19 clinic tested positive for SARS-CoV-2 via PCR, with 547 patients subsequently referred to a specialized Post-COVID Clinic, and 447 of them enrolled in the study. Patient-reported symptoms and paraclinical measures including vitamin D were evaluated in 442 patients. The majority of participants were female (72%, n = 320/442). The consumption of alcohol and number of current smokers were low. Low vitamin D was observed in 26% (n = 115/442) of the patients, most commonly in male participants (odds ratio (OR) = 1.77, 95% confidence interval (CI) (1.12, 2.79), p = 0.014). Additionally, low vitamin D was correlated with a younger mean age of 41 years (standard deviation (SD) = 12) as opposed to 48 years (SD = 13) in patients with normal vitamin D levels (OR = 0.96, 95% CI (0.94, 0.97), p < 0.001). While our study population indicated a potentially higher prevalence of vitamin D insufficiency in this population compared to the general population, no significant differences in prevalence of symptom or symptom severity scores were observed between the low and normal vitamin D groups. In patients in a Post-COVID Clinic, we found no association between vitamin D levels and long COVID symptoms.

Long-term prognosis at 1.5 years after infection with wild-type strain of SARS-CoV-2 and Alpha, Delta, as well as Omicron variants.

OBJECTIVES: Knowledge is limited on how changing SARS-CoV-2 variants may translate into different characteristics and affect the prognosis of patients with long COVID, especially following Omicron variants. We compared long-term prognosis of patients in a Danish Post-COVID Clinic infected with wild-type strain, Alpha, Delta, or Omicron variants as well as the pre-Omicron compared to the Omicron period. METHODS: At enrollment, a Post-COVID symptom Questionnaire (PCQ), and standard health scores, were registered and repeated four times until 1.5 years after infection. PCQ was the primary outcome to assess the severity of long COVID, and Delta PCQ to assess failure to improve. RESULTS: A total of 806 patients were enrolled. Patients infected with Omicron and Delta variants presented with more severe long COVID (median PCQ 43 in Delta vs 38 in wild-type, P = 0.003) and health scores (EuroQol five-dimension five-level-index was 0.70 in Omicron vs 0.76 in wild-type, P = 0.009 and 0.78 pre-Omicron, P = 0.006). At 1.5 years after infection, patients had no clinically meaningful decline in severity of long COVID, and 57% (245/429) of patients failed to improve 1.5 years after infection, with no differences between variants. CONCLUSION: More than half of patients referred to a Post-COVID Clinic failed to improve in long COVID severity 1.5 years after infection regardless of variants of SARS-CoV-2.

Examination of autoantibodies to type I interferon in patients suffering from long COVID.

Long COVID (LC) is an emerging global health concern. The underlying mechanism and pathophysiology remain unclear. Presence of neutralizing autoantibodies against type 1 interferons (IFN) has been established as a predictor of critical COVID-19. We hypothesized that persistent autoimmune activity with autoantibodies against type 1 IFN may contribute to symptoms in patients with LC. Plasma samples and clinical information were obtained from a Danish LC cohort consisting of adult patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Information on symptoms and quality of life was derived from an LC-specific questionnaire and the EQ-5D-5L questionnaire. Detection of type 1 IFN autoantibodies in plasma were performed by ELISA. Samples collected between June, 2020, and September, 2021, from 279 patients were analyzed and compared to a control group of 94 individuals with prior mild SARS-CoV-2 infection who did not develop LC symptoms. In total, five LC patients (1.8%) and 3 (3.2%) of the controls had detectable circulating type 1 IFN autoantibodies. Collectively, prevalence of autoantibodies against type 1 IFN subtypes in our LC cohort were primarily driven by men and did not exceed the prevalence in controls. Thus, in our cohort, anti-type I IFN autoantibodies are unlikely to drive LC symptoms.

Is being a refugee associated with increased 30-day mortality after visiting the emergency department? A register-based cohort study using Danish data.

AIM: Refugees face many challenges that could lead to disparity in quality of care from the health-care system compared with native Danes. These challenges could be language barriers, cultural differences, mental health co-morbidities and socio-economic status (SES). The aim of this study was to compare the 30-day mortality of refugees and native Danes after visiting the emergency department (ED) at Aarhus University Hospital, Denmark. METHODS: In this register-based cohort study linking clinical and socio-demographic data, we included all visits to a major Danish ED from 1 January 2016 to 31 December 2018. According to the predefined analysis plan, we present non-parametric Kaplan-Meier plots and propensity score-weighted analysis. RESULTS: We included 29,257 eligible unique patients of whom 631 were refugees. In the 30-day time period after discharge from the ED, 11 deaths occurred in the group of refugees, resulting in a Kaplan-Meier estimate of 1.8% (95% confidence interval (CI) 0.7-2.8), and 1638 deaths occurred in the group of Danes, resulting in a Kaplan-Meier estimate of 5.9% (95% CI 5.6-6.1). The adjusted 30-day mortality risk difference was 1.6 percentage points (95% CI -2.0 to -1.2 percentage points) lower for refugees compared to native Danes. The 30-day mortality risk difference decreased from approximately 4 to 1.6 percentage points in the adjusted analysis. Thus, there were 16 fewer deaths among refugees within 30 days per 1000 discharged from the ED compared with native Danes when adjusting for age, sex, SES and co-morbidities. CONCLUSIONS: This study shows that refugees had a lower 30-day mortality after visiting the ED compared with native Danes.

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.

Long-Term COVID-19 Smell and Taste Disorders Differ Significantly from Other Post-Infectious Cases.

INTRODUCTION: COVID-19 is causing a wide range of clinical manifestations. Severe complications and long-lasting sequelae have been identified. Thus, olfactory disorders are reported in up to 86% of cases in mild and moderate COVID-19 infections. We present the first study comparing simple and complex post-COVID-19 cases with matched non-COVID-19 post-infectious smell and taste disorders. METHODS: A total of 328 patients were recruited from the University Clinic for Flavour, Balance and Sleep, Ear-nose-throat Department, Goedstrup Hospital, Denmark. A non-COVID -19 post-infectious population of 148 individuals was identified from the Redcap database, and was matched by duration of smell and taste disorders. Post-COVID-19 patients were divided into 99 patients with simple smell and taste disorders (only suffering from smell and taste disorders after COVID-19); and (81 patients with complex smell and taste disorder plus several other post-COVID-19 complaints). Besides patient-reported outcome measures (PROM) questionnaires and quality of life score (QoL), ear-nose-throat examination, Mini-Mental State Examination (MMSE), orthonasal smell test (Sniffing's sticks), retronasal quick test, and taste screening were performed. RESULTS: Cases with post-COVID-19-related smell and taste disorders deviated from non-COVID-19 post-infectious cases; the patients were younger, had a lower occurrence of anosmia/ageusia, and had higher overall smell test scores. In contrast, patients with post-COVID-19-related smell and taste disorders more frequently complained of distorted senses. Parosmia and phantosmia were more prevalent among patients with simple post-COVID-19 complaints than among complex cases and their QoL were more negatively affected. CONCLUSION: Smell and taste function differ significantly between post-COVID-19 and other non-COVID-19 post-viral cases. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:169-174, 2023.

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.

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.

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.

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.

Clinical Management of COVID-19 Patients - An Update.

SARS-CoV-2 virus may cause COVID-19 disease, which causes mild-to-moderate disease in 80% of laboratory-confirmed cases which may be community-managed. A considerable age-dependent mortality is seen among elderly and other at-risk populations but among young and healthy individuals it is < 0.5%. Long-term health issues have been reported following severe COVID-19 requiring hospitalization as well as after cases of mild COVID-19 without hospitalization. Upon receiving COVID-19 suspected patients at hospitals, patients should be isolated and PPE should be worn by all health staff when in contact with the patients. Additionally, patients are tested for the presence of SARS-CoV-2 RNA by PCR, and blood samples are drawn. Imaging is not pivotal for the diagnosis, but chest X-ray is a relevant examination for all and is used to determine severity and treatment need Abnormal findings on CT scans are found in most patients, most frequently peripheral ground-glass opacity and bilateral patchy shadowing are present. Patients are, according to their needs and risks, treated with oxygen therapy, anticoagulation therapy, steroids, antivirals, or immunosupressive drugs on special indications. Convalescent plasma therapy and monoclonal antibodies have a limited role in the treatment, mostly in severely immunocompromised patients. Patients with long-term sequelae should be evaluated in a post-COVID outpatient clinic. The most frequent reported symptoms include cognitive impairment, dyspnea, loss of smell and taste, and mental and physical fatigue although a wide spectrum of symptoms from other organ systems are also reported. The current treatment is based on symptom relief and rehabilitation as there is no documented specific medical treatment.

Long-Term Symptoms among Hospitalized COVID-19 Patients 48 Weeks after Discharge-A Prospective Cohort Study.

Follow-up studies of COVID-19 survivors have been performed to characterize persistence of long-term symptoms, but data are scarce on one year of follow-up. This study provides data from 48 weeks of follow-up after discharge. All patients discharged from the Department of Infectious Diseases at Aarhus University Hospital, Denmark between 1 March and 1 July 2020 were followed for 48 weeks. In total, 45 of 66 eligible patients were interviewed after 48 weeks. The median age was 57 (IQR 51-70) years, the majority were female (53%) and Caucasian (87%). Median BMI was 28.1 (IQR 24.8-32.6) kg/m2. One or more comorbidities were registered among 62% of the patients. In total, 39 out of 45 (87%) interviewed patients reported persistence of at least one symptom 48 weeks after hospitalization with COVID-19. Most frequently reported symptoms were fatigue, dyspnea, and concentration difficulties. This study provides new long-term data following COVID-19, contributing to the accumulating data of COVID-19 sequelae. Many patients suffer long-term sequelae and further research is urgently needed to gain further knowledge of the duration and therapeutic options.

Persistent Symptoms in Patients Recovering From COVID-19 in Denmark.

BACKGROUND: Although persistent symptoms after coronavirus disease 2019 (COVID-19) are emerging as a major complication to the infection, data on the diversity and duration of symptoms are needed. METHODS: Patients aged ≥18 years with a positive polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 who were hospitalized at the Department of Infectious Diseases, Aarhus University Hospital, Denmark, in the period from March 11 to May 15 were offered follow-up after hospitalization. On admission, a comprehensive symptom and medical history was collected, including demographic characteristics, duration of symptoms, comorbidities, and concomitant medications. At discharge, patients were offered follow-up consultations-either by telephone or at an in-person visit-at 6 and 12 weeks at our post-COVID-19 outpatient clinic to assess whether symptoms present at admission had resolved. RESULTS: During the inclusion period, 71 patients were admitted with COVID-19. Of these, 10 patients died, 3 were transferred to another region, 4 declined to participate, and 5 were lost to follow-up before the 12-week evaluation. Thus, 49 patients were included. Overall, 96% reported 1 or more persisting symptoms at 12-week follow-up. The main symptoms were fatigue, dyspnea, cough, chemosensory dysfunction, and headache. CONCLUSIONS: A wide range of persistent symptoms in patients recovering from COVID-19 were present 12 weeks after hospitalization, calling for larger descriptive studies and interdisciplinary research collaborations.

Leukocyte transcript alterations in West-African girls following a booster vaccination with diphtheria-tetanus-pertussis vaccine.

BACKGROUND: Observational studies from low-income countries have shown that the vaccination against diphtheria, tetanus and pertussis (DTP) is associated with excess female mortality due to infectious diseases. METHODS: To investigate possible changes in gene expression after DTP vaccination, we identified a group of nine comparable West African girls, from a biobank of 356 children, who were due to receive DTP booster vaccine at age 18 months. As a pilot experiment we extracted RNA from blood samples before, and 6 weeks after, vaccination to analyze the coding transcriptome in leukocytes using expression microarrays, and ended up with information from eight girls. The data was further analyzed using dedicated array pathway and network software. We aimed to study whether DTP vaccination introduced a systematic alteration in the immune system in girls. RESULTS: We found very few transcripts to alter systematically. Those that did mainly belonged to the Interferon (IFN) signalling pathway. We scrutinized this pathway as well as the Interleukin (IL) pathways. Two out of eight showed a down-regulated IFN pathway and two showed an up-regulated IFN pathway. The two with down-regulated IFN pathway had also down-regulated IL-6 pathway. In the study of networks, two of the girls stood out as not having the inflammatory response as top altered network. CONCLUSION: The transcriptome changes following DTP booster vaccination were subtle, but although the material was small, it was possible to identify sub groups that deviate from each other, mainly in the IFN response.

Does the effect of vitamin A supplements depend on vaccination status? An observational study from Guinea-Bissau.

Objective Vitamin A supplementation (VAS) is estimated to reduce all-cause mortality by 24%. Previous studies indicate that the effect of VAS may vary with vaccination status. The authors evaluated the effect of VAS provided in campaigns on child survival overall and by sex and vaccination status at the time of supplementation. Design Observational cohort study. Setting and participants The study was conducted in the urban study area of the Bandim Health Project in Guinea-Bissau. The authors documented participation or non-participation in two national vitamin A campaigns in December 2007 and July 2008 for children between 6 and 35 months of age. Vaccination status was ascertained by inspection of vaccination cards. All children were followed prospectively. Outcome measures Mortality rates for supplemented and non-supplemented children were compared in Cox models providing mortality rate ratios (MRRs). Results The authors obtained information from 93% of 5567 children in 2007 and 90% of 5799 children in 2008. The VAS coverage was 58% in 2007 and 68% in 2008. Mortality in the supplemented group was 1.5% (44 deaths/2873 person-years) and 1.6% (20 deaths/1260 person-years) in the non-supplemented group (adjusted MRR=0.78 (0.46; 1.34)). The effect was similar in boys and girls. Vaccination cards were seen for 86% in 2007 and 84% in 2008. The effect of VAS in children who had measles vaccine as their last vaccine (2814 children, adjusted MRR=0.34 (0.14; 0.85)) differed from the effect in children who had diphtheria-tetanus-pertussis vaccine as their last vaccine (3680 children, adjusted MRR=1.29 (0.52; 3.22), p=0.04 for interaction). Conclusion The effect of VAS differed by most recent vaccination, being beneficial after measles vaccine but not after diphtheria-tetanus-pertussis vaccine.