Early clues regarding the pathogenesis of long-COVID.

Intense investigation into the predictors and determinants of post-acute sequelae of SARS-CoV-2 infection (PASC), including 'long COVID', is underway. Recent studies provide clues to the mechanisms that might drive this condition, with the goal of identifying host or virus factors that can be intervened upon to prevent or reverse PASC.

Long COVID in Pakistan: a cross-sectional analysis of health and psychosocial outcomes.

According to the World Health Organization-led Delphi consensus, long COVID corresponds to the occurrence of symptoms beyond twelve weeks after the onset of acute COVID-19 illness that cannot be explained by alternate diagnosis. This cross-sectional study aimed to analyse the impacts of long COVID on general health and psychosocial well-being. For this study, the participants were interviewed either face to face or via telephone, and their responses were recorded on a questionnaire capturing information on demographics, COVID-19 status, duration of symptoms and long COVID symptoms. The psychosocial impacts of the pandemic were assessed using scales like Short Mood and feeling questionnaire (sMFQ), Warwick-Edinburgh Mental Well-being Scale (WEMWBS), Generalized Anxiety Disorder Assessment (GAD-7) and Perceived Stress Scale (PSS). Regression analysis was conducted to analyse the predictors of long COVID. A total of 300 participants were interviewed, of which 155 (52%) had COVID-19 illness. Of these 54 (35%) had persistent symptoms for a period of more than 12 weeks classified as long COVID. Muscle problems and fatigue were the most frequent (14.7%) symptoms encountered, followed by breathing problems (12.6%) and cognitive issues (12.6%). The symptoms of decrease in appetite and confusion or disorientation during the initial phase of the infection were associated with long COVID. The majority of the participants (83.3%) had moderate level of perceived stress, while moderate to severe levels of stress were observed in 17.3% of the individuals. Moreover, a high level of positive mental well-being was also observed. This study highlights the need for further research into the clinical aspects and implications of long COVID in Pakistan and emphasizes the importance of ongoing support for affected individuals.

Genetic risk factors for severe and fatigue dominant long COVID and commonalities with ME/CFS identified by combinatorial analysis.

BACKGROUND: Long COVID is a debilitating chronic condition that has affected over 100 million people globally. It is characterized by a diverse array of symptoms, including fatigue, cognitive dysfunction and respiratory problems. Studies have so far largely failed to identify genetic associations, the mechanisms behind the disease, or any common pathophysiology with other conditions such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that present with similar symptoms. METHODS: We used a combinatorial analysis approach to identify combinations of genetic variants significantly associated with the development of long COVID and to examine the biological mechanisms underpinning its various symptoms. We compared two subpopulations of long COVID patients from Sano Genetics' Long COVID GOLD study cohort, focusing on patients with severe or fatigue dominant phenotypes. We evaluated the genetic signatures previously identified in an ME/CFS population against this long COVID population to understand similarities with other fatigue disorders that may be triggered by a prior viral infection. Finally, we also compared the output of this long COVID analysis against known genetic associations in other chronic diseases, including a range of metabolic and neurological disorders, to understand the overlap of pathophysiological mechanisms. RESULTS: Combinatorial analysis identified 73 genes that were highly associated with at least one of the long COVID populations included in this analysis. Of these, 9 genes have prior associations with acute COVID-19, and 14 were differentially expressed in a transcriptomic analysis of long COVID patients. A pathway enrichment analysis revealed that the biological pathways most significantly associated with the 73 long COVID genes were mainly aligned with neurological and cardiometabolic diseases. Expanded genotype analysis suggests that specific SNX9 genotypes are a significant contributor to the risk of or protection against severe long COVID infection, but that the gene-disease relationship is context dependent and mediated by interactions with KLF15 and RYR3. Comparison of the genes uniquely associated with the Severe and Fatigue Dominant long COVID patients revealed significant differences between the pathways enriched in each subgroup. The genes unique to Severe long COVID patients were associated with immune pathways such as myeloid differentiation and macrophage foam cells. Genes unique to the Fatigue Dominant subgroup were enriched in metabolic pathways such as MAPK/JNK signaling. We also identified overlap in the genes associated with Fatigue Dominant long COVID and ME/CFS, including several involved in circadian rhythm regulation and insulin regulation. Overall, 39 SNPs associated in this study with long COVID can be linked to 9 genes identified in a recent combinatorial analysis of ME/CFS patient from UK Biobank. Among the 73 genes associated with long COVID, 42 are potentially tractable for novel drug discovery approaches, with 13 of these already targeted by drugs in clinical development pipelines. From this analysis for example, we identified TLR4 antagonists as repurposing candidates with potential to protect against long term cognitive impairment pathology caused by SARS-CoV-2. We are currently evaluating the repurposing potential of these drug targets for use in treating long COVID and/or ME/CFS. CONCLUSION: This study demonstrates the power of combinatorial analytics for stratifying heterogeneous populations in complex diseases that do not have simple monogenic etiologies. These results build upon the genetic findings from combinatorial analyses of severe acute COVID-19 patients and an ME/CFS population and we expect that access to additional independent, larger patient datasets will further improve the disease insights and validate potential treatment options in long COVID.

Long-term effect of COVID-19 infection on kidney function among COVID-19 patients followed in post-COVID-19 recovery clinics in British Columbia, Canada.

BACKGROUND: We investigated the effect of Post-Acute COVID Syndrome or "long-COVID" on kidney function among patients followed in post-COVID recovery clinics (PCRC) in British Columbia, Canada. METHODS: Long-COVID patients referred to PCRC between July 2020 to April 2022, aged ≥18 years who had an estimated glomerular filtration rate (eGFR) value recorded at 3 months from the coronavirus disease 2019 (COVID-19) diagnosis (index) date were included. Those requiring renal replacement therapy prior to index date were excluded. Primary outcome was change in eGFR and urine albumin-creatinine ratio (UACR) after COVID-19 infection. The proportion of patients in each of the six eGFR categories (<30, 30-44, 45-59, 60-89, 90-120 and >120 mL/min/1.73 m2) and three UACR categories (<3, 3-30 and >30 mg/mmol) in all of the study time points were calculated. Linear mixed model was used to investigate change in eGFR over time. RESULTS: The study sample included 2212 long-COVID patients. Median age was 56 years, 51% were male. Half (∼47%-50%) of the study sample had normal eGFR (≥90 mL/min/1.73 m2) from COVID-19 diagnosis to 12 months post-COVID and <5% of patients had an eGFR <30 mL/min/1.73 m2. There was an estimated 2.96 mL/min/1.73 m2 decrease in eGFR within 1 year after COVID-19 infection that was equivalent to 3.39% reduction from the baseline. Decline in eGFR was highest in patients hospitalized for COVID-19 (6.72%) followed by diabetic patients (6.15%). More than 40% of patients were at risk of CKD. CONCLUSIONS: People with long-COVID experienced a substantial decline in eGFR within 1 year from the infection date. The prevalence of proteinuria appeared to be high. Close monitoring of kidney function is prudent among patients with persistent COVID-19 symptoms.

Short and mid-term characteristics of COVID-19 disease course in athletes: A high-volume, single-center study.

INTRODUCTION: At the pandemic's beginning, significant concern has risen about the prevalence of myocardial involvement after SARS-CoV-2 infection. We assessed the cardiovascular burden of SARS-CoV-2 in a large cohort of athletes and identified factors that might affect the disease course. We included 633 athletes in our study on whom we performed extensive cardiology examinations after recovering from SARS-CoV-2 infection. More than half of the athletes (n = 322) returned for a follow-up examination median of 107 days after the commencement of their infection. RESULTS: Troponin T positivity was as low as 1.4% of the athletes, where the subsequently performed examinations did not show definitive, ongoing myocardial injury. Altogether, 31% of the athletes' rapid training rebuild was hindered by persistent or reoccurring symptoms. Female athletes reported a higher prevalence of return to play (RTP) symptoms than their male counterparts (34% vs. 19%, p = 0.005). The development of long COVID symptoms was independently predicted by increasing age and acute symptoms' severity in a multiple regression model (AUC 0.75, CI 0.685-0.801). Athletes presenting with either or both cough and ferritin levels higher than >150 µg/L had a 4.1x (CI 1.78-9.6, p = 0.001) higher odds ratio of developing persistent symptoms. CONCLUSION: While SARS-CoV-2 rarely affects the myocardium in athletes, about one in three of them experience symptoms beyond the acute phase. Identifying those athletes with a predisposition to developing long-standing symptoms may aid clinicians and trainers in finding the optimal return-to-play timing and training load rebuild pace.

Evidence mapping and review of long-COVID and its underlying pathophysiological mechanism.

PURPOSE: Apart from the global disease burden of acute COVID-19 disease, the health complications arising after recovery have been recognized as a long-COVID or post-COVID-19 syndrome. Evidences of long-COVID symptoms involving various organ systems are rapidly growing in literature. The objective was to perform a rapid review and evidence mapping of systemic complications and symptoms of long-COVID and underlying pathophysiological mechanisms. METHODS: Publications reporting clinical trials, observational cohort studies, case-control studies, case-series, meta-analysis, and systematic reviews, focusing on the squeal of the disease, consequences of COVID-19 treatment/hospitalization, long-COVID, chronic COVID syndrome, and post acute COVID-19 were reviewed in detail for the narrative synthesis of frequency, duration, risk factors, and pathophysiology. RESULTS: The review highlights that pulmonary, neuro-psychological, and cardiovascular complications are major findings in most epidemiological studies. However, dysfunctional gastrointestinal, endocrine, and metabolic health are recent findings for which underlying pathophysiological mechanisms are poorly understood. Analysis of the clinical trial landscape suggests that more than 50% of the industry-sponsored trials are focused on pulmonary symptoms. In contrast to the epidemiological trends and academic trials, cardiovascular complications are not a focus of industry-sponsored trials, suggestive of the gaps in the research efforts. CONCLUSION: The gap in epidemiological trends and academic trials, particularly concerning cardiovascular complications not being a focus of industry-sponsored trials is suggestive of the gaps in research efforts and longer follow-up durations would help identify other long-COVID-related health issues such as reproductive health and fertility.

Gender differences in symptomatology, socio-demographic information and quality of life in Spanish population with long COVID condition: a cross-sectional study.

Introduction: Long COVID patients experience a decrease in their quality of life due to the symptomatology produced by the disease. It is also important to understand how long COVID affects both men and women. The objective of this study is to examine the impact of long COVID symptomatology on the quality of life of Spanish adults from a gender perspective. Methods: An observational and cross-sectional study was carried out. Participants were able to complete an online questionnaire using an online platform. A sample of 206 people participated in the study. Results: The 80.6% of the sample were women with a mean age of 46.51 (±8.28) and the 19.4% were men with a mean age of 48.03 (±9.50). The medium score in the PAC19-QoL test was 141.47 (±24.96) and segmented by gender, 141.65 (±23.95) for women and 140.82 (±28.66) for men. The most common symptoms in women were muscle and joint pain (94.6%), fatigue (94.0%), discomfort (92.2%), difficulty concentrating (91.0%), and memory loss (88.6%). For men the symptoms included muscle and joint pain (97.5%) and fatigue (97.5%) both occupying first position, discomfort (92.0%), difficulty concentrating (90.0%), mood disturbances (90.0%), and memory loss (87.5%). The chi-square test showed statistical significance (p < 0.005) for socio-demographic information, quality of life scores, and long COVID symptoms by intensities. Conclusion: This study shows that there are gender differences in the way that long COVID is experienced.

Long COVID is associated with severe cognitive slowing: a multicentre cross-sectional study.

Background: COVID-19 survivors may experience a wide range of chronic cognitive symptoms for months or years as part of post-COVID-19 conditions (PCC). To date, there is no definitive objective cognitive marker for PCC. We hypothesised that a key common deficit in people with PCC might be generalised cognitive slowing. Methods: To examine cognitive slowing, patients with PCC completed two short web-based cognitive tasks, Simple Reaction Time (SRT) and Number Vigilance Test (NVT). 270 patients diagnosed with PCC at two different clinics in UK and Germany were compared to two control groups: individuals who contracted COVID-19 before but did not experience PCC after recovery (No-PCC group) and uninfected individuals (No-COVID group). All patients with PCC completed the study between May 18, 2021 and July 4, 2023 in Jena University Hospital, Jena, Germany and Long COVID clinic, Oxford, UK. Findings: We identified pronounced cognitive slowing in patients with PCC, which distinguished them from age-matched healthy individuals who previously had symptomatic COVID-19 but did not manifest PCC. Cognitive slowing was evident even on a 30-s task measuring simple reaction time (SRT), with patients with PCC responding to stimuli ∼3 standard deviations slower than healthy controls. 53.5% of patients with PCC's response speed was slower than 2 standard deviations from the control mean, indicating a high prevalence of cognitive slowing in PCC. This finding was replicated across two clinic samples in Germany and the UK. Comorbidities such as fatigue, depression, anxiety, sleep disturbance, and post-traumatic stress disorder did not account for the extent of cognitive slowing in patients with PCC. Furthermore, cognitive slowing on the SRT was highly correlated with the poor performance of patients with PCC on the NVT measure of sustained attention. Interpretation: Together, these results robustly demonstrate pronounced cognitive slowing in people with PCC, which distinguishes them from age-matched healthy individuals who previously had symptomatic COVID-19 but did not manifest PCC. This might be an important factor contributing to some of the cognitive impairments reported in patients with PCC. Funding: Wellcome Trust (206330/Z/17/Z), NIHR Oxford Health Biomedical Research Centre, the Thüringer Aufbaubank (2021 FGI 0060), German Forschungsgemeinschaft (DFG, FI 1424/2-1) and the Horizon 2020 Framework Programme of the European Union (ITN SmartAge, H2020-MSCA-ITN-2019-859890).

Comparative Analysis of Lymphocyte Populations in Post-COVID-19 Condition and COVID-19 Convalescent Individuals.

Reduced lymphocyte counts in peripheral blood are one of the most common observations in acute phases of viral infections. Although many studies have already examined the impact of immune (dys)regulation during SARS-CoV-2 infection, there are still uncertainties about the long-term consequences for lymphocyte homeostasis. Furthermore, as persistent cellular aberrations have been described following other viral infections, patients with "Post-COVID-19 Condition" (PCC) may present similarly. In order to investigate cellular changes in the adaptive immune system, we performed a retrospective analysis of flow cytometric data from lymphocyte subpopulations in 106 patients with confirmed SARS-CoV-2 infection who received medical care at our institution. The patients were divided into three groups according to the follow-up date; laboratory analyses of COVID-19 patients were compared with 28 unexposed healthy controls. Regarding B lymphocyte subsets, levels of IgA + CD27+, IgG + CD27+, IgM + CD27- and switched B cells were significantly reduced at the last follow-up compared to unexposed healthy controls (UHC). Of the 106 COVID-19 patients, 56 were clinically classified as featuring PCC. Significant differences between PCC and COVID-19 convalescents compared to UHC were observed in T helper cells and class-switched B cells. However, we did not detect specific or long-lasting immune cellular changes in PCC compared to the non-post-COVID-19 condition.

Short- and long-term effects of imatinib in hospitalised COVID-19 patients: A randomised trial.

OBJECTIVES: We studied the short- and long-term effects of imatinib in hospitalised COVID-19 patients. METHODS: Participants were randomised to receive standard of care (SoC) or SoC with imatinib. Imatinib dosage was 400mg daily until discharge (max 14 days). Primary outcomes were mortality at 30 days and 1 year. Secondary outcomes included recovery, quality of life and long COVID symptoms at 1 year. We also performed a systematic review and meta-analysis of randomised trials studying imatinib for 30-day mortality in hospitalised COVID-19 patients. RESULTS: We randomised 156 patients (73 in SoC and 83 in imatinib). Among patients on imatinib, 7.2% had died at 30 days and 13.3% at 1 year and in SoC 4.1% and 8.2% (adjusted HR 1.35, 95% CI 0.47-3.90). At 1-year, self-reported recovery occurred in 79.0% in imatinib and in 88.5% in SoC (RR 0.91, 0.78-1.06). We found no convincing difference in quality of life or symptoms. Fatigue (24%) and sleep issues (20%) frequently bothered patients at one year. In the meta-analysis, imatinib was associated with a mortality risk ratio of 0.73 (0.32-1.63; low certainty evidence). CONCLUSIONS: The evidence raises doubts regarding benefit of imatinib in reducing mortality, improving recovery and preventing long COVID symptoms in hospitalised COVID-19 patients.

A systematic review of quantitative EEG findings in Fibromyalgia, Chronic Fatigue Syndrome and Long COVID.

Fibromyalgia Syndrome (FMS), Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID (LC) are similar multisymptom clinical syndromes but with difference in dominant symptoms in each individual. There is existing and emerging literature on possible functional alterations of the central nervous system in these conditions. This review aims to synthesise and appraise the literature on resting-state quantitative EEG (qEEG) in FMS, ME/CFS and LC, drawing on previous research on FMS and ME/CFS to help understand neuropathophysiology of the new condition LC. A systematic search of MEDLINE, Embase, CINHAL, PsycINFO and Web of Science databases for articles published between December 1994 and September 2023 was performed. Out of the initial 2510 studies identified, 17 articles were retrieved that met all the predetermined selection criteria, particularly of assessing qEEG changes in one of the three conditions compared to healthy controls. All studies scored moderate to high quality on the Newcastle-Ottawa scale. There was a general trend for decreased low-frequency EEG band activity (delta, theta, and alpha) and increased high-frequency EEG beta activity in FMS, differing to that found in ME/CFS. The limited LC studies included in this review focused mainly on cognitive impairments and showed mixed findings not consistent with patterns observed in FMS and ME/CFS. Our findings suggest different patterns of qEEG brainwave activity in FMS and ME/CFS. Further research is required to explore whether there are phenotypes within LC that have EEG signatures similar to FMS or ME/CFS. This could inform identification of reliable diagnostic markers and possible targets for neuromodulation therapies tailored to each clinical syndrome.

The presence of symptoms within 6 months after COVID-19: a single-center longitudinal study.

BACKGROUND: Characterizing the post-COVID health conditions is helpful to direct patients to appropriate healthcare. AIMS: To describe the presence of symptoms in COVID-19 patients within 6 months after diagnosis and to investigate the associated factors in terms of reporting symptoms. METHODS: Data of DEU-COVIMER (a telephone interview-based COVID-19 follow-up center established in a tertiary care hospital) was analyzed for SARS-CoV-2 RNA positive participants aged ≥ 18 years from November 1st, 2020, to May 31st, 2021. Symptom frequencies were stratified by demographic and clinical characteristics at one, three, and 6 months after diagnosis. With the patients who had symptoms at baseline, generalized estimating equations were applied to identify the factors associated with reporting of symptoms. RESULTS: A total of 5610 patients agreed to participate in the study. Symptom frequency was 37.2%, 21.8%, and 18.2% for the first, third, and sixth months. Tiredness/fatigue, muscle or body aches, and dyspnea/difficulty breathing were the most common symptoms in all time frames. In multivariate analysis, older age, female gender (odds ratio OR 1.74, 95% confidence interval 1.57-1.93), bad economic status (OR 1.37, 1.14-1.65), current smoking (OR 1.15, 1.02-1.29), being fully vaccinated before COVID-19 (OR 0.53, 0.40-0.72), having more health conditions (≥ 3 conditions, OR 1.78, 1.33-2.37), having more symptoms (> 5 symptoms, OR 2.47, 2.19-2.78), and hospitalization (intensive care unit, OR 2.18, 1.51-3.14) were associated with reporting of symptoms. CONCLUSIONS: This study identifies risk factors for patients who experience post-COVID-19 symptoms. Healthcare providers should appropriately allocate resources prioritizing the patients who would benefit from post-COVID rehabilitation.

Point-of-Care Ultrasound of Post-acute COVID-19 Syndrome: A Prospective Cohort Study.

Introduction Acute COVID-19 patients can suffer from chronic symptoms known as post-acute sequelae of SARS-CoV-2 infection (PASC). Point-of-care ultrasound (POCUS) is established in acute COVID, but its utility in PASC is unclear. We sought to determine the incidence of cardiac and pulmonary abnormalities with POCUS in patients with PASC in a COVID-19 recovery clinic. Methods This prospective cohort study included adults (>18 years old) presenting with cardiopulmonary symptoms to the COVID-19 recovery clinic. A lung ultrasound and standard bedside echocardiogram were performed by ultrasound-trained physicians. Images were interpreted in real time by the performing sonographer and independently by a blinded ultrasound faculty member. Discrepancies in interpretation were addressed by consensus review. A modified Soldati score was calculated by the sum of the scores in each of the 12 lung zones, with each zone score ranging from 0 to 3 (maximum score of 36). The score was then compared to clinical outcomes and outpatient testing.  Results Between April and July 2021, 41 patients received POCUS examinations, with 24 of those included in the study. In all, 15 out of 24 (62.5%) had a normal lung ultrasound. Of the nine subjects with lung abnormalities, the median modified Soldati score was 2. Three patients had trivial pericardial effusions, and all had normal left and right ventricular size and function. Conclusion The majority (62.5%) of patients presenting to the PASC clinic had a normal pulmonary ultrasound, and the vast majority (87.5%) had normal cardiac ultrasounds. These findings suggest that cardiopulmonary symptoms in PASC may be from etiologies not well evaluated by POCUS.

Post-COVID-19 Syndrome Mechanisms, Prevention and Management.

As the population of patients recovering from COVID-19 grows, post COVID-19 challenges are recognizing by ongoing evidences at once. Long COVID is defined as a syndrome with a range of persistent symptoms that remain long after (beyond 12 weeks) the acute SARS-CoV-2 infection. Studies have shown that long COVID can cause multi-organ damages with a wide spectrum of manifestations. Many systems, but not limited to, including respiratory, cardiovascular, nervous, gastrointestinal, and musculoskeletal systems, are involved in long COVID. Fatigue and dyspnea are the most common symptoms of long COVID. Long COVID-19 may be driven by tissue damage caused by virus-specific pathophysiologic changes or secondary to pathological long-lasting inflammatory response because of viral persistence, immune dysregulation, and autoimmune reactions. Some risk factors like sex and age, more than five early symptoms, and specific biomarkers have been revealed as a probable long COVID predicator discussed in this review. It seems that vaccination is the only way for prevention of long COVID and it can also help patients who had already long COVID. Managing long COVID survivors recommended being in a multidisciplinary approach, and a framework for identifying those at high risk for post-acute COVID-19 must be proposed. Possible therapeutic options and useful investigation tools for follow-up are suggested in this review. In sum, as evidence and researches are regularly updated, we provide the current understanding of the epidemiology, clinical manifestation, suspected pathophysiology, associated risk factors, and treatment options of long COVID in this review.

High prevalence of persistent symptoms and reduced health-related quality of life 6 months after COVID-19.

Background: The long-term sequelae after COVID-19 constitute a challenge to public health and increased knowledge is needed. We investigated the prevalence of self-reported persistent symptoms and reduced health-related quality of life (HRQoL) in relation to functional exercise capacity, 6 months after infection, and explored risk factors for COVID-19 sequalae. Methods: This was a prospective, multicenter, cohort study including 434 patients. At 6 months, physical exercise capacity was assessed by a 1-minute sit-to-stand test (1MSTST) and persistent symptoms were reported and HRQoL was evaluated through the EuroQol 5-level 5-dimension (EQ-5D-5L) questionnaire. Patients with both persistent symptoms and reduced HRQoL were classified into a new definition of post-acute COVID syndrome, PACS+. Risk factors for developing persistent symptoms, reduced HRQoL and PACS+ were identified by multivariable Poisson regression. Results: Persistent symptoms were experienced by 79% of hospitalized, and 59% of non-hospitalized patients at 6 months. Hospitalized patients had a higher prevalence of self-assessed reduced overall health (28 vs. 12%) and PACS+ (31 vs. 11%). PACS+ was associated with reduced exercise capacity but not with abnormal pulse/desaturation during 1MSTST. Hospitalization was the most important independent risk factor for developing persistent symptoms, reduced overall health and PACS+. Conclusion: Persistent symptoms and reduced HRQoL are common among COVID-19 survivors, but abnormal pulse and peripheral saturation during exercise could not distinguish patients with PACS+. Patients with severe infection requiring hospitalization were more likely to develop PACS+, hence these patients should be prioritized for clinical follow-up after COVID-19.

Cognitive and functional connectivity impairment in post-COVID-19 olfactory dysfunction.

OBJECTIVES: To explore the neuropsychological profile and the integrity of the olfactory network in patients with COVID-19-related persistent olfactory dysfunction (OD). METHODS: Patients with persistent COVID-19-related OD underwent olfactory assessment with Sniffin' Sticks and neuropsychological evaluation. Additionally, both patients and a control group underwent brain MRI, including T1-weighted and resting-state functional MRI (rs-fMRI) sequences on a 3 T scanner. Morphometrical properties were evaluated in olfaction-associated regions; the rs-fMRI data were analysed using graph theory at the whole-brain level and within a standard parcellation of the olfactory functional network. All the MR-derived quantities were compared between the two groups and their correlation with clinical scores in patients were explored. RESULTS: We included 23 patients (mean age 37 ± 14 years, 12 females) with persistent (mean duration 11 ± 5 months, range 2-19 months) COVID-19-related OD (mean score 23.63 ± 5.32/48, hyposmia cut-off: 30.75) and 26 sex- and age-matched healthy controls. Applying population-derived cut-off values, the two cognitive domains mainly impaired were visuospatial memory and executive functions (17 % and 13 % of patients). Brain MRI did not show gross morphological abnormalities. The lateral orbital cortex, hippocampus, and amygdala volumes exhibited a reduction trend in patients, not significant after the correction for multiple comparisons. The olfactory bulb volumes did not differ between patients and controls. Graph analysis of the functional olfactory network showed altered global and local properties in the patients' group (n = 19, 4 excluded due to artifacts) compared to controls. Specifically, we detected a reduction in the global modularity coefficient, positively correlated with hyposmia severity, and an increase of the degree and strength of the right thalamus functional connections, negatively correlated with short-term verbal memory scores. DISCUSSION: Patients with persistent COVID-19-related OD showed an altered olfactory network connectivity correlated with hyposmia severity and neuropsychological performance. No significant morphological alterations were found in patients compared with controls.

Associations of Post-Acute COVID syndrome with physiological and clinical measures 10 months after hospitalization in patients of the first wave.

BACKGROUND: For a better understanding of the factors underlying the Post-Acute COVID Syndrome, we studied the relationship between symptoms and functional alterations in COVID-19 patients 10 months after hospitalization. METHODS: One-hundred-one patients hospitalized between March 1st and June 30th 2020 participated in a follow-up visit for an assessment of clinical history, comorbidities, lung function, physical capacity and symptoms, including the SGRQ for health-related quality of life, PHQ-9-D for depression, and SOMS-2 J for somatoform disorders. Data were analyzed by univariate comparisons and multiple logistic regression analyses. RESULTS: Median age was 60 years, 42% were female, 76% had at least one comorbidity, the median length of the hospital stay was 8 days, 19% had been on the ICU. The most prevalent symptoms included shortness of breath (49%), fatigue (49%) and cognitive impairment (39%). Signs of major depression (PHQ-9-D ≥ 10) occurred in 28%/2% (p < 0.05) of patients with/without self-reported cognitive impairment, with median total SGRQ score being 25.4/5.3 (p < 0.05). There were associations between shortness of breath and BMI, SGRQ and hemoglobin levels; between fatigue, SGRQ and PHQ-9-D; and between cognitive impairment and PHQ-9-D (p < 0.05 each) but not with lung function or physical capacity. Characteristics of the acute disease were not related to symptoms. CONCLUSIONS: The findings demonstrate that 10 months after discharge from a hospital stay due to COVID-19, the percentages of patients with symptoms were high. Symptoms showed a consistent pattern but could not be attributed to altered lung function or physical capacity. Our results suggest a role for alternative etiologies including psychosocial factors.

Unbalanced IDO1/IDO2 Endothelial Expression and Skewed Keynurenine Pathway in the Pathogenesis of COVID-19 and Post-COVID-19 Pneumonia.

Despite intense investigation, the pathogenesis of COVID-19 and the newly defined long COVID-19 syndrome are not fully understood. Increasing evidence has been provided of metabolic alterations characterizing this group of disorders, with particular relevance of an activated tryptophan/kynurenine pathway as described in this review. Recent histological studies have documented that, in COVID-19 patients, indoleamine 2,3-dioxygenase (IDO) enzymes are differentially expressed in the pulmonary blood vessels, i.e., IDO1 prevails in early/mild pneumonia and in lung tissues from patients suffering from long COVID-19, whereas IDO2 is predominant in severe/fatal cases. We hypothesize that IDO1 is necessary for a correct control of the vascular tone of pulmonary vessels, and its deficiency in COVID-19 might be related to the syndrome's evolution toward vascular dysfunction. The complexity of this scenario is discussed in light of possible therapeutic manipulations of the tryptophan/kynurenine pathway in COVID-19 and post-acute COVID-19 syndromes.

Neurocognitive and Psychosocial Characteristics of Pediatric Patients With Post-Acute/Long-COVID: A Retrospective Clinical Case Series.

OBJECTIVE: Studies suggest a large number of patients have persistent symptoms following COVID-19 infection-a condition termed "long COVID." Although children and parents often report cognitive difficulties after COVID, very few if any studies have been published including neuropsychological testing. METHODS: A retrospective chart review was completed for the first 18 patients referred for a neuropsychological evaluation from a multidisciplinary pediatric post-COVID clinic. The neuropsychological screening battery assessed verbal fluency and category switching, attention, working memory, processing speed, and verbal learning and memory. Patients' caregivers also completed standardized questionnaires regarding day-to-day mood and behavior. RESULTS: At intake, the most common neurologic symptoms reported by caregivers were attention problems (83.3%), fatigue/lethargy (77.7%), sleep disturbance (77.7%), dizziness/vertigo (72.2%), and headaches (72.2%). On rating scales, most caregivers endorsed concerns for depressed mood and anxiety (14/15 and 12/15). A large proportion of patients had difficulties with attention (9/18) and depressed mood/anxiety (13/18) before COVID. On cognitive testing, the majority of the patients performed within or above broad average range (≥16th percentile) across most domains. However, a little over half of the patients performed below average on auditory attention measures. CONCLUSIONS: Within our clinically referred sample, children who reported lingering cognitive symptoms after COVID-19 often had a preexisting history of attention and/or mood and anxiety concerns. Many of these patients performed below average in attention testing, but it remains to be seen whether this was due to direct effects of COVID, physical symptoms, and/or preexisting difficulties with attention or mood/anxiety.

Validation Criteria for PETCO2 Kinetics during the Hyperventilation Provocation Test in the Diagnosis of Idiopathic Hyperventilation Syndrome.

Background: The hyperventilation provocation test (HPTest) is a diagnostic tool for idiopathic hyperventilation syndrome (HVS), encountered in some long-COVID patients. However, interpretation of the HPTest remains unclear regarding the relevant PETCO2 values to focus on and whether subjective symptoms should be considered. This study aimed to re-evaluate objective HPTest results for diagnosing HVS by determining accurate PETCO2 kinetics in two groups of patients previously screened via the Nijmegen questionnaire (NQ). Methods: The kinetics of PETCO2 during the HPTest were mathematically modeled and compared between 37 HVS patients (NQ ≥23/64) and 37 healthy controls (NQ <23/64) matched for gender, age, and body dimensions. AUC values with sensitivity and specificity were calculated, and analysis was monitored in a validation cohort of 152 routine HPTests. Results: A threshold value of a less than 12.8 mmHg increment of PETCO2 at the 5th minute of the recovery phase of the HPTest diagnosed HVS patients with excellent sensitivity (0.92) and specificity (0.84). These results were confirmed in the validation cohort, highlighting the presence of 24% false positives/negatives when diagnosing on the basis of complaints in the NQ. Conclusions: For HVS diagnosis, we suggest considering the HPTest, which can more reliably reflect the mechanisms of CO2 homeostasis and the response of the respiratory center to a stimulus, regardless of the subjective onset of symptoms.