The Psychological Ability to Cope Reduced Infections During the Pandemic: A Two-Year Population-Based Study of The Determinants of 123 Million COVID-19 Test Results in Denmark (preprint)

During the COVID-19 pandemic, a key concern for authorities was to identify and activate the psychological states most likely to motivate the public to engage in protective behavior such as physical distancing and hygienic protection. While feelings of fear and threat were rampant during the pandemic, theories of health psychology have highlighted appraisals related to the ability to cope (e.g., the feeling of being able to cost-effectively adhere to government advice) and argued that coping appraisals are superior predictors of motivations to protect the self against risks. In this study, we provide a massive population-based comparison of the association between, on the one hand, threat appraisals, and coping appraisals and, on the other hand, protection against actual infection during the COVID-19 pandemic. To this end, we utilize a unique data infrastructure from Denmark that couple surveys of 8 % of the adult Danish population (N= 386.633) with the individual results of all 123 million COVID-19 tests performed in Denmark during 23 months of the COVID-19 pandemic. Overall, controlling for a comprehensive range of sociodemographic measures and employing panel data to bolster internal validity, we observe that stronger coping appraisals are consistently associated with lower individual probability of COVID-19 infection risk. We find no con-sistent evidence for a similar association for threat appraisals. Threat appraisals rather seem to index – to some extent, accurately – individual feelings of infection exposure. As appeals to fear also have unintended negative consequences (includ-ing anxiety, fatigue, and stigmatization), the findings provide strong empirical support for relying on coping-oriented public health communication in future societal crises in the domain of health and beyond.

Enhancing EQ-5D-5L sensitivity in capturing the most common symptoms in post COVID-19 patients: an exploratory cross-sectional study with focus on fatigue, memory/concentration problems and dyspnea dimensions (preprint)

This study aimed to determine whether the EQ-5D-5L tool captures the most common persistent symptoms, such as fatigue, memory/concentration problems and dyspnea in patients with post COVID-19 conditions, and if adding these symptoms improves the explained variance of the health-related quality of life (HRQoL). In this exploratory cross-sectional study, two cohorts of Swedish patients (n=177) with a history of COVID-19 infection answeared a questionnaire covering sociodemographic characteristics, clinical factors and HRQoL assessed using EQ-5D-5L with the Visual Analogue Scale (EQ-VAS). Spearman rank correlation and multiple regression analyses were employed to investigate the extent to which the most common persistent symptoms such as fatigue, memory/concentration problems and dyspnea were explained by the EQ-5D-5L. The explanatory power of EQ-5D-5L for EQ-VAS was also analysed, both with and without inclusion of symptom(s). We found that the EQ-5D-5L dimensions partly captured fatigue and memory/concentration problems but performed poorly in capturing dyspnea. Specifically, the EQ-5D-5L explained 55% of the variance in memory/concentration problems, 47% in fatigue and only 14% in dyspnea. Adding fatigue to the EQ-5D-5L increased the explained variance of the EQ-VAS by 5.7%, while the addition of memory/concentration problems and dyspnea had a comparatively smaller impact on the explained variance. Our study highlights the EQ-5D-5L’s strength in capturing fatigue and memory/concentration problems in post COVID-19 patients. However, it also underscores the challenges in assessing dyspnea in this group. Fatigue emerged as a notably influential symptom, significantly enhancing the EQ-5D-5L's predictive ability to for the EQ-VAS score in these patients.

Factors Predicting Health‐Related Quality of Life in Post-COVID Patients: A cross-sectional study (preprint)

Background Post-COVID conditions can occur in every system of the body with physical and mental impacts resulting in a poor quality of life. Therefore, knowledge of the factors affecting health-related quality of life is important for treating patients with post-COVID conditions. This was a descriptive correlational research study with a cross-sectional research design aiming to determine the predictive power of body mass index (BMI), sleep quality, fatigue, and social support to improve health-related quality of life among patients with post-COVID conditions. Methods The study enrolled 126 male and female patients with post-COVID conditions aged 18 years and above. All patients were admitted to the outpatient departments of two tertiary hospitals in Bangkok, Thailand, for examination and treatment from April to September 2023. The research instruments included personal data and illness record questionnaires, Pittsburgh Sleep Quality Index, Functional Assessment of Chronic Illness Therapy-Fatigue Scale, Revised Thai version of the Multidimensional Scale of Perceived Social Support, and EuroQol Group-5 Dimension-5 Levels. The patient basic data were analyzed using descriptive statistics. Predictive power was analyzed using linear multiple regression with statistical significance set at 0.05. Results The patient with post-COVID conditions had health-related quality of life at mean of 0.826 (SD = 0.102). Multiple regression analysis revealed that all of the independent could account for 68.40% (R2 = 0.684, F = 65.39, p < 0.001) of the variance explained of health-related quality of life. The strongest predictor was fatigue (β = 0.673, p < 0.001), followed by social support (β = 0.214, p < 0.001) and sleep quality (β = −0.127, p = 0.033).   Conclusion Patients with post-COVID conditions experienced negative effects on health-related quality of life. Therefore, nurses and health care providers should assess health-related quality of life and its determinant factors, namely fatigue, sleep quality, and social support. Moreover, programs should be created to relieve fatigue or promote sleep quality in patients with post-COVID condition to achieve a good health-related quality of life in the future.

Long COVID in Children and Adolescents: A Retrospective Controlled Cohort Study from Iran (preprint)

Background: After recovering from the acute phase of COVID-19, some of the infected children manifest long COVID symptoms. The present study aims to identify long COVID symptoms in children and adolescents admitted to hospitals in Bushehr, Iran, during 2021 to 2023, and compare them with the non-affected group. Methods: This retrospective cohort study was conducted on 141 children and adolescents with COVID-19 and 141 non-affected peers. The data were collected using the data recorded in the patients’ records, conducting telephone interviews and completing the prevalent long COVID symptom form. Results: The mean age of the hospitalized children with COVID-19 was 79±5.24 months old, 57.4% of whom were boys. Also, 46 individuals of the infected group (32.6%) manifested long COVID symptoms. The most prevalent symptoms included fatigue (54.3%), impaired attention or concentration (41.3%) and depression or anxiety symptoms (34.7%). Significant correlation was found between disease severity and muscle and joint pain (P=0.025) as well as between length of hospital stay and cough (P=0.022), weight loss (P=0.047) and depression or anxiety symptoms (P=0.008). Older age [(6-11 y; OR=3.18, CI=1.03-9.88); (12≥ y; OR= 4.57, CI=1.40-14.96)] and having history of smoking or being exposed to secondhand smoke (OR= 12.45, CI= 3.14-49.36) were considered as risk factors for long COVID. Conclusions: Informing the public about smoking or being exposed to smoke as risk factors for long COVID, in addition to its other hazards, is of particular importance. Informing the healthcare staff and general public about the most prevalent symptoms of long COVID could be effective in timely diagnosis and treatment as well as reducing families’ stress burden.

Greater Role of Cognitive Impairment Over Fatigue in Post-COVID-19 Quality of Life: A Post-Hoc Analysis of a Randomized Controlled Trial (preprint)

BackgroundPost COVID-19 Condition (PCC) is a common and debilitating condition with significant reports of fatigue and psychosocial impairment globally. The extent to which cognitive symptoms and fatigue contribute to reduced quality of life in affected individuals remains clear. MethodsThis is a post-hoc analysis of a randomized, double-blind, placebo-controlled clinical trial that evaluated the effect of vortioxetine on cognitive function in adults with PCC. The post-hoc analysis herein aimed to determine the overall effect of baseline cognitive function [as measured by the Digit Symbol Substitution Test (DSST)] and baseline fatigue severity [as measured by the Fatigue Severity Scale (FSS)] on baseline health-related quality of life (HRQoL) [as measured by the 5-item World Health Organisation Well-Being Index (WHO-5)]. ResultsA total of 200 participants were enrolled in the primary trial. Due to missing baseline data, our statistical analysis included baseline measures of 147 individuals. Our generalized linear model analysis revealed a significant positive correlation between DSST-measured objective cognitive function and self-reported WHO-5-measured HRQoL ({beta} = 0.069, 95% CI [0.006, 0.131], p = 0.032). In contrast, our analysis revealed a significant negative correlation between FSS and WHO-5 scores ({beta} = -0.016, 95% CI [-0.021, -0.011], p < 0.001). The beta-coefficient ratio ({beta}DSST / {beta}FSS = 0.069 / 0.016) is calculated as 4.313. ConclusionsOverall, we observed that increased cognitive function was associated with increased HRQoL at baseline in adults with PCC. Moreover, we observed that increased severity of fatigue symptoms was associated with decreased HRQoL at baseline in adults with PCC. Furthermore, we observed that an improvement in cognitive function would have a four-fold greater impact on HRQoL than the effect generated by improvement in fatigue.

Cardiac safety after AstraZeneca COVID-19 vaccination: A cohort observational study (preprint)

Background Vaccination is a well-established part of preventive and public health medicine but is not without risk. Most of the side effects related to COVID-19 vaccines are minor including local symptoms at the injection site and some systemic symptoms, such as fatigue, headache, and fever. Some preliminary reports mentioned a more serious side effect; myocarditis seen after certain COVID-19 vaccines. The purpose of this study was to reveal any decrease in left ventricular systolic function in patients receiving the AstraZeneca COVID-19 vaccine compared to healthy individuals who did not receive the vaccine.Methods This study included 150 people divided into two equal groups; the case group included individuals who received AstraZeneca COVID-19 vaccines, and the sex- and age-matched control group included healthy individuals who did not receive any of the COVID-19 vaccines. Echocardiographic parameters for assessment of systolic function were evaluated after full vaccination.Results By the end of the study, no difference was found between the case and control groups regarding the left ventricular ejection fraction (LVEF), the S' wave of the mitral valve, or the global longitudinal strain (GLS).Conclusions AstraZeneca COVID-19 vaccination was not associated with myocardial damage, as evaluated by 2D echocardiography, tissue Doppler, and speckle tracking echocardiography.

The impact of wildtype SARS-CoV-2 on fatigue and quality of life: prevalence of post COVID-19 condition in a Dutch population-based serosurveillance cohort. (preprint)

Background: Our aim was to assess the relationship between (time since) wild-type SARS-CoV-2 infection and health-related quality of life (HRQoL) and fatigue as endpoints linked to Post COVID-19 condition (PCC). Methods: Participants [≥]15 years were selected from the February 2021 round of the population-based PIENTER Corona study. We investigated the association between (time since) SARS-COV-2 infection and health outcomes: HRQoL (health utility (SF-6D); physical health and mental health (both SF-12)) and fatigue (CIS-fatigue) using multivariable logistic regression analyses adjusted for age, sex, educational level, number of comorbidities, COVID-19 vaccination status, and the intensity of restrictions. For each outcome, multivariable logistic regression models were fitted at cut-off points selected based on the cumulative distribution of those uninfected. Results: Results shown correspond to the cut-off point related to the worst off 15% of each outcome. Significant differences between those uninfected (n=4,614) and cases infected [≤]4 months ago (n=368) were observed for health utility (OR [95%CI]: 1.6 [1.2-2.2]), physical health (OR [95%CI]: 1.7 [1.3-2.3]) and fatigue (OR [95%CI]: 1.6 [1.2-2.0]), but not for mental health. There were no significant differences between uninfected and cases infected >4 months ago (n=345) for all outcomes. Conclusions: In a Dutch population-based cohort of seroconverted individuals, those infected with wild-type SARS-CoV-2 [≤]4 months ago more often reported poor health utility and physical health and were more often severely fatigued compared to those uninfected (at the 15% cut-off). HRQoL and fatigue remained below the detection limit for those infected >4 months ago, suggesting a relatively low prevalence of PCC.

Interventions for the management of post COVID-19 condition (long COVID): Protocol for a living systematic review & network meta-analysis (preprint)

Background: Up to 15% of survivors of COVID-19 infection experience long-term health effects, including fatigue, myalgia, and impaired cognitive function, termed post COVID-19 condition or long COVID. Several trials that study the benefits and harms of various interventions to manage long COVID have been published and hundreds more are planned or are ongoing. Trustworthy systematic reviews that clarify the benefits and harms of interventions are critical to promote evidence-based practice. Objective To create and maintain a living systematic review and network meta-analysis addressing the benefits and harms of pharmacologic and non-pharmacologic interventions for the treatment and management of long COVID. Methods Eligible trials will randomize adults with long COVID, to pharmacologic or non-pharmacologic interventions, placebo, sham, or usual care. We will identify eligible studies by searches of MEDLINE, EMBASE, CINAHL, PsycInfo, AMED, and CENTRAL, from inception, without language restrictions. Reviewers will work independently and in duplicate to screen search records, collect data from eligible trials, including trial and patient characteristics and outcomes of interest, and assess risk of bias. Our outcomes of interest will include fatigue, pain, post-exertional malaise, changes in education or employment status, cognitive function, mental health, dyspnea, quality of life, patient-reported physical function, recovery, and serious adverse events. For each outcome, when possible, we will perform a frequentist random-effects network meta-analysis. When there are compelling reasons to suspect that certain interventions are only applicable or effective for a subtype of long COVID, we will perform separate network meta-analyses. The GRADE approach will guide our assessment of the certainty of evidence. We will update our living review biannually, upon the publication of a seminal trial, or when new evidence emerges that may change clinical practice. Conclusion This living systematic review and network meta-analysis will provide comprehensive, trustworthy, and up-to-date summaries of the evidence addressing the benefits and harms of interventions for the treatment and management of long COVID. We will make our findings available publicly and work with guideline producing organizations to inform their recommendations.

Incidence, risk factors, and clinical symptom profile of reinfection during Omicron-dominated COVID-19 outbreak in Hong Kong: A retrospective cohort study (preprint)

Background: Despite the declaration from World Health Organization of the end of the COVID-19 pandemic, reinfection persists and continues to strain the global healthcare system. With the emergence of the most recent variant of SARS-CoV-2 named JN.1, retrospective analysis of epidemiological characteristics of previous cases involving the Omicron variant is essential to provide references for preventing reinfection caused by the ongoing new SARS-Cov-2 variants. Methods: This retrospective cohort study included 6325 patients infected with SARS-CoV-2 during the Omicron-dominated outbreak (from December 2021 to May 2022) in Hong Kong. Statistical analysis was conducted to demonstrate the epidemiological characteristics and a logistic regression model was utilized to identify risk factors associated with reinfection. Results: The Omicron reinfection incidence was 5.18% (n = 353). No significant difference was observed in receiving mRNA (BNT162b2) vaccine and inactivated (CoronaVac) vaccine between reinfection and non-reinfection groups (p>0.05). Risk factors were identified as female gender (p<0.001), longer infection duration (p<0.05), comorbidity of eyes, ear, nose, throat disease (p<0.01), and severe post-infection impact on daily life and work (p<0.05), while equal or larger than 70 years old (p<0.05) and vaccination after primary infection (p<0.01) were associated with a lower risk of reinfection. The prevalence of most symptoms after reinfection was lower than the first infection, except for fatigue. Conclusion: No significant difference in mRNA (BNT162b2) vaccine and inactivated (CoronaVac) vaccine against reinfection. Post-infection vaccination could lower the risk of reinfection, which potentially inform the development of preventive measures including vaccination policies against potential new SARS-Cov-2 variants.

Link Between the G Protein-Coupled Receptor (GPCR), SARS-CoV-2 Spike Protein, ACE2, Vaccines, and Long COVID (preprint)

The knowledge of COVID-19 impact on the human body has increased rapidly. Although many people recover from COVID-19, some continue to experience persistent symptoms that have been identified as Long COVID. This condition can have a severe impact on quality of life, and it remains a significant concern for medical professionals and researchers. One of the key components of the SARS-CoV-2 virus that enables it to enter human cells is the spike (S) protein. Recent studies have revealed a complex network of interactions between G proteins, spike (S) protein, and the Renin-Angiotensin System (RAS) may be responsible, at least in part, for long COVID. SARS-CoV-2 can also affect the brain, leading to neurological symptoms such as confusion, memory loss, and fatigue. Increasing evidence suggests that COVID-19 is not just a respiratory illness since it is likely that the virus could influence signal transduction pathways such as G-protein-coupled receptor (GPCR), among others, in the brain, either directly or indirectly, affecting neural functions. These interactions with the spike (S) protein and RAS, alongside the brain, are complex and require deep research to understand their implications for Long COVID-19 manifestation fully. While recent research has shed light on the complex interactions between G proteins, spike (S) protein, the brain, and the angiotensin system, this article explores these interconnected pathways and their implications for long COVID-19 manifestations. The present review summarises current research on different molecular mechanisms in Long COVID pathophysiology and may help identify possible targets or new strategies for the diagnosis and treatment.

Prevalence and factors influencing long COVID among primary healthcare workers after epidemic control policy adjustment in Jiangsu, China (preprint)

Objective: This study aims to evaluate the prevalence of long COVID infections and their influencing factors among primary HCWs after epidemic control policy adjustment in Jiangsu. Methods: : A self-designed questionnaire was administered through on-site surveys among primary HCWs in five counties and districts within Jiangsu Province from July 4 to July 20, 2023. Results: : The prevalence of long COVID among primary HCWs stood at 12.61% (95% confidence interval (CI) of 11.67%-13.55%). The most common long COVID symptoms were hypomnesia (4.90%), sleep difficulties (2.73%), fatigue (2.35%), disturbances in the reproductive system (1.93%), hair loss (1.85%), and myalgia/arthralgia (1.51%). Multivariate logistic regression revealed that older age groups (30-45 years (adjusted odds ratios (aOR) =1.93, 95%CI: 1.44-2.58), 45-60 years (aOR=2.82, 95%CI: 2.07-3.84)), females (aOR=1.26, 95%CI: 1.03-1.55), and higher work stress (high stress (aOR=1.52, 95%CI: 1.24-1.86), extremely high stress (aOR=1.37, 95%CI: 1.03-1.82)) were more prone to long COVID. Conversely, individuals with educational attainment below the bachelor’s degree (aOR=0.67, 95%CI: 0.55-0.82) and those who received four or more doses of the COVID-19 vaccine (aOR=0.55, 95%CI: 0.33-0.92) were at a reduced risk. Conclusion: To mitigate the incidence of long COVID, healthcare providers and authorities should implement effective measures, including optimizing work-rest schedules and actively advocating for vaccination.

Tracking Persistent Symptoms in Scotland (TraPSS): A Longitudinal Prospective Cohort Study of COVID-19 Recovery After Mild Acute Infection (preprint)

Background: COVID-19 disease results in disparate responses between individuals and has led to the emergence of Long-COVID, characterized by persistent and cyclical symptomology. To understand the complexity of Long-COVID, the importance of symptom surveillance and prospective longitudinal studies is evident. Methods: A 9-month longitudinal prospective cohort study was conducted within Scotland (n=287), using a mobile app to determine the proportion of recovered individuals, those with persistent symptoms, common symptoms, and associations with gender and age. Results: 3.1% of participants experienced symptoms at month 9, meeting the criteria for Long-COVID, as defined by the NICE terminology. Fatigue, cough, and muscle pain were the most common symptoms at baseline, with fatigue persisting the longest, while symptoms like cough improved rapidly. Older age increased the likelihood of reporting pain and cognitive impairment. Female gender increased the likelihood of headaches and post-exertional malaise (PEM), and increased recovery time from fatigue and PEM. Conclusions: The majority of people fully recover from acute COVID-19, albeit often slowly. Age and gender play a role in symptom burden and recovery rates, emphasizing the need for tailored approaches to Long-COVID management. Further analysis is required to determine the characteristics of the individuals still reporting ongoing symptoms months after initial infection to identify risk factors and potential predictors for the development of Long-COVID.

The association between loneliness and mental health disorders in older people after the COVID-19 pandemic (preprint)

Background Acknowledging the exacerbated impact of the COVID-19 pandemic on the mental health status of the general population, particularly the older population, this study aimed to explore the association between loneliness and mental health disorders in older people after the COVID-19 pandemic.Methods A cross-sectional survey using the SHARE database was conducted from June to August 2020 amid the COVID-19 pandemic.Results The sample comprised 847 participants, including 393 (46.4%) men, with an overall mean age of 74.6 years (sd = 6.7 years). Concerning mental health indicators, 441 (52.1%) reported feelings of nervousness, 384 (45.3%) experienced sadness or depression, 349 (41.2%) encountered sleeping difficulties, and 280 (33.1%) reported experiencing loneliness often or some of the time. The results revealed increased loneliness feelings for women who had worse health, increased fear of falling, dizziness, heightened fatigue, anxiety, depression, and concurrent health and sleep problems. Notably, age and medication had no impact on feeling lonely.Conclusions The pandemic has adversely affected the mental well-being of older population. These findings provide valuable insights for the development of targeted strategies to prevent mental health problems.

Molecular hydrogen for outpatients with Covid-19 (Hydro-Covid): a phase 3, randomised, triple-blinded, adaptive, placebo-controlled, multicentre trial (preprint)

Background: Due to its antioxidative, anti-inflammatory, anti-apoptosis, and antifatigue properties, molecular hydrogen (H2) is potentially a novel therapeutic gas for acute coronavirus disease 2019 (COVID-19) patients. Aim To determine the efficacy and safety profile of hydrogen rich water (HRW) to reduce the risk of progression of COVID-19. Design and settings We conducted a phase 3, triple-blind, randomized, placebo-controlled trial to evaluate treatment with HRW started within 5 days after the onset of signs or symptoms in primary care patients with mild-to-moderate, laboratory-confirmed COVID-19 and at least one risk factor for severe COVID-19 illness. Method Participants were randomly assigned to receive HRW or placebo twice daily for 21 days. The composite primary endpoint was the incidence of clinical worsening (dyspnea, fatigue) associated with a need for oxygen therapy, hospitalization or death at day-14; the incidence of adverse events was the primary safety end point. Results A total of 675 participants were followed up until day-30. 337 in the HRW group and 338 in the placebo group. Baseline characteristics were similar in the two groups. HRW was not superior to placebo in preventing clinical worsening at day-14: in H2 group, 46.1% met a clinical deterioration, 43.5% in the placebo group, Hazard Ratio 1.09, 90% confidence interval [0.90-1.31]. One death was reported in the H2 group and 2 in the placebo group at day-30. Adverse events were reported in 91 (27%) and 89 (26.2%) participants respectively. Conclusion Twice-daily ingestion of HRW from the onset of COVID-19 symptoms for 21 days did not reduce clinical worsening. Keywords: COVID-19; Molecular Hydrogen; Administration, Oral; Primary health care; Outcome Assessment;

PFC/M1 activation and excitability: a longitudinal cohort study on fatigue symptoms in healthcare workers post-COVID-19 (preprint)

Background Fatigue is one of the most common neurological symptoms reported post coronavirus disease 2019 (COVID-19) infection. In order to establish effective early intervention strategies, more emphasis should be placed on the correlation between fatigue and cortical neurophysiological changes, especially in healthcare workers, who are at a heightened risk of COVID-19 infection.Methods A prospective cohort study was conducted involving 29 COVID-19 medical workers and 24 healthy controls. The assessment included fatigue, sleep and health quality, psychological status, and physical capacity. Functional near-infrared spectroscopy (fNIRS) was employed to detect activation of brain regions. Bilateral primary motor cortex (M1) excitabilities were measured using single- and paired-pulse transcranial magnetic stimulation. Outcomes were assessed at 1, 3, and 6 months into the disease course.Results At 1-month post-COVID-19 infection, 37.9% of patients experienced severe fatigue symptoms, dropping to 10.3% at 3 months. Interestingly, the remarkable decreased activation/excitability of bilateral prefrontal lobe (PFC) and M1 were closely linked to fatigue symptoms after COVID-19. Notably, greater increase in M1 region excitability correlated with more significant fatigue improvement. Re-infected patients exhibited lower levels of brain activation and excitability compared to single-infection patients.Conclusions Both single infection and reinfection of COVID-19 lead to decreased activation and excitability of the PFC and M1. The degree of excitability improvement in the M1 region correlates with a greater recovery in fatigue. Based on these findings, targeted interventions to enhance and regulate the excitability of M1 may represent a novel strategy for COVID-19 early rehabilitation.Trial registration The Ethics Review Committee of Xijing Hospital, No. KY20232051-F-1, registered February 3, 2023. The Chinese Clinical Trial Registry, ChiCTR2300068444, registered February 20, 2023. https://www.chictr.org.cn

Modelling long COVID using Bayesian networks (preprint)

Motivated by the ambiguity of operational case definitions for long COVID and the impact of the lack of a common causal language on long COVID research, in early 2023 we began developing a research framework on this post-acute infection syndrome. We used directed acyclic graphs (DAGs) and Bayesian networks (BNs) to depict the hypothesised mechanisms of long COVID in an agnostic fashion. The DAGs were informed by the evolving literature and subsequently refined following elicitation workshops with domain experts. The workshops were structured online sessions guided by an experienced facilitator. The causal DAG aims to summarise the hypothesised pathobiological pathways from mild or severe COVID-19 disease to the development of pulmonary symptoms and fatigue over four different time points. The DAG was converted into a BN using qualitative parametrisation. These causal models aim to assist the identification of disease endotypes, as well as the design of randomised controlled trials and observational studies. The framework can also be extended to a range of other post-acute infection syndromes.

Cold case: COVID-19-triggered type 1 cryoglobulinemia (preprint)

A 42-year-old male was referred to the internal medicine department because of renal failure and persistent malaise after a recent SARS-CoV-2 infection. Blood results showed anemia and severe renal insufficiency (hemoglobin of 6.4 mmol/l and a creatinine of 194 umol/l). Additional tests revealed a type I cryoglobulinemia with a cryoprecipitate composed of biclonal IgM (kappa and lambda). Further investigations on the cryoprecipitate revealed that the immunoglobulins were directed against SARS-CoV-2 antigens. In the meanwhile, our patient noticed improvement of his symptoms accompanied by resolution of laboratory abnormalities. Three months later, the cryoglobulin could no longer be detected. Type 1 cryoglobulinemia is usually associated with lymphoproliferative disorders and is characterized by various symptoms caused by cryoprecipitates occluding small blood vessels. This is, to our knowledge, the first case of type I cryoglobulinemia with proven precipitation of SARS-CoV-19 antibodies. COVID-19 induced cryoglobulinemia appears to have a mild disease course and to be self-limiting upon viral clearance.

Predictors of moderate-to-severe side-effects following COVID-19 mRNA booster vaccination: A prospective cohort study among primary health care providers in Belgium. (preprint)

Background COVID-19 vaccine effectiveness declines months after vaccination. Therefore, it is likely that during the next few years, people may be repeatedly offered a booster vaccine to enhance humoral immunity levels. A growing number of people are questioning whether the benefits of a booster vaccine outweigh the side-effects.Objective This study aims (1) to identify the most frequently reported side-effects after different doses of COVID-19 mRNA vaccines, (2) and the longest lasting symptoms; and (3) to predict the likelihood of having moderate-to-severe side-effects after a booster COVID-19 mRNA vaccine given individual- and vaccine-specific characteristics.Design, setting, and participants : Secondary analysis of a prospective cohort study in primary health care providers (PHCPs) in Belgium conducted between December 2020 and December 2021, and in February-March 2023.Methods In nine subsequent surveys over a period of 2 years vaccine dose-number and side-effects after COVID-19 vaccines were collected. A Generalized Estimation Equations approach on the data of the first and second booster dose was used to investigate the probability of having moderate-to-severe side-effects after mRNA booster vaccination. Predictive performance of a binary classifier was assessed by looking at discrimination (i.e., quantified in terms of the area under the receiver operating characteristic curve). The final prediction model was validated using data with regard to the third booster by assessing misclassification rate, sensitivity and specificity.Results In total, 11% of the PHCPs had moderate-to-severe side-effects after their booster COVID-19 mRNA vaccine. The most common side-effects of COVID-19 mRNA doses included fatigue, local pain at the injection site, general pains, and headache. These side-effects typically lasted for a median of 1 to 2 days. The final model included five predictors: sex, alcohol consumption, history of moderate-to-severe side-effects after any previous dose, recent COVID-19 infection, and the booster dose-number (first, second). Having experienced moderate-to-severe side-effects after any previous dose was the strongest predictor of moderate-to-severe side-effects following an mRNA vaccine booster, with an odds ratio (OR) of 3.64 (95% CI: 2.80–4.75). The OR for female sex was 1.49 (95% CI: 1.21–1.84) implying that females have a higher odds of moderate-to-severe side-effects following booster vaccination. The differences in effect for booster dose-number, alcohol consumption and recent COVID-19 infection was not significant.Conclusion and Relevance: COVID-19 mRNA booster vaccination implies a low prevalence of moderate-to-severe side-effects among PHCPs, with a short median duration of symptoms if any. The strongest predictors are a history of moderate-to-severe side-effects after any previous dose and being female. These reassuring findings can help addressing concerns about booster vaccination and encourage their uptake.Trial Registration: NCT04779424

Exercise Intolerance in Long Covid After 24 Months From Severe Acute Disease: is There Room for Improvement? (preprint)

Introduction: Long COVID is a complex and multisystemic condition, where dyspnea, fatigue, post-exertional malaise, cognitive impairment, decreased functional capacity, and deterioration in quality of life are the most incident clinical features. Few studies have reported cardiopulmonary alterations 24 months after severe COVID-19 infection.  Objective: to evaluate the functional capacity of individuals with persistent symptoms after severe COVID-19 infection compared to control individuals without symptomatic COVID or mild COVID after 24 months.  Methods: This is a case-control study assessing 34 individuals divided into 2 groups (severe COVID-19 with long COVID and a control group consisting of asymptomatic/mild acute COVID-19 with no long COVID) regarding functional capacity by 6-minute walk test (6MWT) associated with gas analysis, spirometry, respiratory muscle strength and quality of life. Results: During the 6MWT, an important lower heart rate (HR) was observed for the COVID group, with greater exertional perception, a significant decrease in the distance covered, and a low value of O2 uptake (V̇O2) and minute ventilation, in addition to very low quality of life scores, especially in aspects of functional capacity and physical limitations.  Conclusion: individuals who have severe COVID-19 and persist with symptoms have low functional capacity, low V̇O2, low HR behavior, and low quality of life. 

Exploring the Efficacy of Shirodhara as an Add-on Therapy for Alleviating Post-COVID Anxiety and Depression: A Case Study (preprint)

Background This study explores post-COVID-19 psychological challenges in a 31-year-old female patient—manifesting as Anxiety, fatigue, weakness, irritability, anger, and concentration issues. The treatment approach combines SSRI and Clonazepam medications with Shirodhara therapy using Balashwagandhadi taila, presenting a novel and comprehensive intervention strategy.Methods The patient was evaluated using recognized scales, such as HAM-A, HDRS, PHQ-9, and QOL. Additionally, monitoring serum cortisol levels served as a potential physiological marker. The integrative treatment approach addresses psychological symptoms and potential underlying physiological mechanisms.Results Significant improvement is observed across various domains, evidenced by reduced HAM-A, HDRS, and PHQ-9 scores and enhanced QOL. Post-Shirodhara therapy, a notable increase in serum cortisol levels from 3.09 ug/dL to 11.76 ug/dL, suggesting a correlation with clinical improvements.Conclusion This case underscores Shirodhara's promising role as an adjunctive therapy for post-COVID-19 Anxiety and depression. Findings advocate further exploring integrative approaches in post-viral psychological care, emphasizing addressing psychological and potential physiological aspects for holistic recovery.