Tag: covid-19

The association of insomnia with long COVID: An international collaborative study (ICOSS-II)

Abstract:

Objective: There is evidence of a strong association between insomnia and COVID-19, yet few studies have examined the relationship between insomnia and long COVID. This study aimed to investigate whether COVID-19 patients with pre-pandemic insomnia have a greater risk of developing long COVID and whether long COVID is in turn associated with higher incident rates of insomnia symptoms after infection.

Methods: Data were collected cross-sectionally (May-Dec 2021) as part of an international collaborative study involving participants from 16 countries. A total of 2311 participants (18-99 years old) with COVID-19 provided valid responses to a web-based survey about sleep, insomnia, and health-related variables. Log-binomial regression was used to assess bidirectional associations between insomnia and long COVID. Analyses were adjusted for age, sex, and health conditions, including sleep apnea, attention and memory problems, chronic fatigue, depression, and anxiety.

Results: COVID-19 patients with pre-pandemic insomnia showed a higher risk of developing long COVID than those without pre-pandemic insomnia (70.8% vs 51.4%; adjusted relative risk [RR]: 1.33, 95% confidence interval [CI]: 1.07-1.65). Among COVID-19 cases without pre-pandemic insomnia, the rates of incident insomnia symptoms after infection were 24.1% for short COVID cases and 60.6% for long COVID cases (p < .001). Compared with short COVID cases, long COVID cases were associated with an increased risk of developing insomnia symptoms (adjusted RR: 2.00; 95% CI: 1.50-2.66).

Conclusions: The findings support a bidirectional relationship between insomnia and long COVID. These findings highlight the importance of addressing sleep and insomnia in the prevention and management of long COVID.

Source: Chen SJ, Morin CM, Ivers H, Wing YK, Partinen M, Merikanto I, Holzinger B, Espie CA, De Gennaro L, Dauvilliers Y, Chung F, Yordanova J, Vidović D, Reis C, Plazzi G, Penzel T, Nadorff MR, Matsui K, Mota-Rolim S, Leger D, Landtblom AM, Korman M, Inoue Y, Hrubos-Strøm H, Chan NY, Bjelajac AK, Benedict C, Bjorvatn B. The association of insomnia with long COVID: An international collaborative study (ICOSS-II). Sleep Med. 2023 Dec;112:216-222. doi: 10.1016/j.sleep.2023.09.034. Epub 2023 Oct 24. PMID: 37922783. https://www.sciencedirect.com/science/article/abs/pii/S1389945723003672

Complement dysregulation is a predictive and therapeutically amenable feature of long COVID

Abstract:

Background Long COVID encompasses a heterogeneous set of ongoing symptoms that affect many individuals after recovery from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The underlying biological mechanisms nonetheless remain obscure, precluding accurate diagnosis and effective intervention. Complement dysregulation is a hallmark of acute COVID-19 but has not been investigated as a potential determinant of long COVID.

Methods We quantified a series of complement proteins, including markers of activation and regulation, in plasma samples from healthy convalescent individuals with a confirmed history of infection with SARS-CoV-2 and age/ethnicity/gender/infection/vaccine-matched patients with long COVID.

Findings Markers of classical (C1s-C1INH complex), alternative (Ba, iC3b), and terminal pathway (C5a, TCC) activation were significantly elevated in patients with long COVID. These markers in combination had a receiver operating characteristic predictive power of 0.794. Other complement proteins and regulators were also quantitatively different between healthy convalescent individuals and patients with long COVID. Generalized linear modeling further revealed that a clinically tractable combination of just four of these markers, namely the activation fragments iC3b, TCC, Ba, and C5a, had a predictive power of 0.785.

Conclusions These findings suggest that complement biomarkers could facilitate the diagnosis of long COVID and further suggest that currently available inhibitors of complement activation could be used to treat long COVID.

Source: Kirsten Baillie, Helen E Davies, Samuel B K Keat, Kristin Ladell, Kelly L Miners, Samantha A Jones, Ermioni Mellou, Erik J M Toonen, David A Price, B Paul Morgan, Wioleta M Zelek. Complement dysregulation is a predictive and therapeutically amenable feature of long COVID.
medRxiv 2023.10.26.23297597; doi: https://doi.org/10.1101/2023.10.26.23297597 https://www.medrxiv.org/content/10.1101/2023.10.26.23297597v1.full-text (Full text)

Post-COVID exercise intolerance is associated with capillary alterations and immune dysregulations in skeletal muscles

Abstract:

The SARS-CoV-2 pandemic not only resulted in millions of acute infections worldwide, but also in many cases of post-infectious syndromes, colloquially referred to as “long COVID”. Due to the heterogeneous nature of symptoms and scarcity of available tissue samples, little is known about the underlying mechanisms.

We present an in-depth analysis of skeletal muscle biopsies obtained from eleven patients suffering from enduring fatigue and post-exertional malaise after an infection with SARS-CoV-2. Compared to two independent historical control cohorts, patients with post-COVID exertion intolerance had fewer capillaries, thicker capillary basement membranes and increased numbers of CD169+ macrophages. SARS-CoV-2 RNA could not be detected in the muscle tissues.

In addition, complement system related proteins were more abundant in the serum of patients with PCS, matching observations on the transcriptomic level in the muscle tissue. We hypothesize that the initial viral infection may have caused immune-mediated structural changes of the microvasculature, potentially explaining the exercise-dependent fatigue and muscle pain.

Source: Aschman, T., Wyler, E., Baum, O. et al. Post-COVID exercise intolerance is associated with capillary alterations and immune dysregulations in skeletal muscles. acta neuropathol commun 11, 193 (2023). https://doi.org/10.1186/s40478-023-01662-2 https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-023-01662-2 (Full text)

Severe mental illness, race/ethnicity, multimorbidity and mortality following COVID-19 infection: nationally representative cohort study

Abstract:

Background: The association of COVID-19 with death in people with severe mental illness (SMI), and associations with multimorbidity and ethnicity, are unclear.

Aims: To determine all-cause mortality in people with SMI following COVID-19 infection, and assess whether excess mortality is affected by multimorbidity or ethnicity.

Method: This was a retrospective cohort study using primary care data from the Clinical Practice Research Database, from February 2020 to April 2021. Cox proportional hazards regression was used to estimate the effect of SMI on all-cause mortality during the first two waves of the COVID-19 pandemic.

Results: Among 7146 people with SMI (56% female), there was a higher prevalence of multimorbidity compared with the non-SMI control group (n = 653 024, 55% female). Following COVID-19 infection, the SMI group experienced a greater risk of death compared with controls (adjusted hazard ratio (aHR) 1.53, 95% CI 1.39-1.68). Black Caribbean/Black African people were more likely to die from COVID-19 compared with White people (aHR = 1.22, 95% CI 1.12-1.34), with similar associations in the SMI group and non-SMI group (P for interaction = 0.73). Following infection with COVID-19, for every additional multimorbidity condition, the aHR for death was 1.06 (95% CI 1.01-1.10) in the SMI stratum and 1.16 (95% CI 1.15-1.17) in the non-SMI stratum (P for interaction = 0.001).

Conclusions: Following COVID-19 infection, patients with SMI were at an elevated risk of death, further magnified by multimorbidity. Black Caribbean/Black African people had a higher risk of death from COVID-19 than White people, and this inequity was similar for the SMI group and the control group.

Source: Das-Munshi J, Bakolis I, Bécares L, Dyer J, Hotopf M, Ocloo J, Stewart R, Stuart R, Dregan A. Severe mental illness, race/ethnicity, multimorbidity and mortality following COVID-19 infection: nationally representative cohort study. Br J Psychiatry. 2023 Nov;223(5):518-525. doi: 10.1192/bjp.2023.112. PMID: 37876350; PMCID: PMC7615273. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7615273/ (Full text)

Chronic Fatigue and Dysautonomia following COVID-19 Vaccination Is Distinguished from Normal Vaccination Response by Altered Blood Markers

Abstract:

SARS-CoV-2 mRNA vaccination can entail chronic fatigue/dysautonomia tentatively termed post-acute COVID-19 vaccination syndrome (PACVS). We explored receptor autoantibodies and interleukin-6 (IL-6) as somatic correlates of PACVS. Blood markers determined before and six months after first-time SARS-CoV-2 vaccination of healthy controls (N = 89; 71 females; mean/median age: 39/49 years) were compared with corresponding values of PACVS-affected persons (N = 191; 159 females; mean/median age: 40/39 years) exhibiting chronic fatigue/dysautonomia (≥three symptoms for ≥five months after the last SARS-CoV-2 mRNA vaccination) not due to SARS-CoV-2 infection and/or confounding diseases/medications.

Normal vaccination response encompassed decreases in 11 receptor antibodies (by 25-50%, p < 0.0001), increases in two receptor antibodies (by 15-25%, p < 0.0001) and normal IL-6. In PACVS, serological vaccination-response appeared significantly (p < 0.0001) altered, allowing discrimination from normal post-vaccination state (sensitivity = 90%, p < 0.0001) by increased Angiotensin II type 1 receptor antibodies (cut-off ≤ 10.7 U/mL, ROC-AUC = 0.824 ± 0.027), decreased alpha-2B adrenergic receptor antibodies (cut-off ≥ 25.2 U/mL, ROC-AUC = 0.828 ± 0.025) and increased IL-6 (cut-off ≤ 2.3 pg/mL, ROC-AUC = 0.850 ± 0.022). PACVS is thus indicated as a somatic syndrome delineated/detectable by diagnostic blood markers.

Source: Semmler A, Mundorf AK, Kuechler AS, Schulze-Bosse K, Heidecke H, Schulze-Forster K, Schott M, Uhrberg M, Weinhold S, Lackner KJ, Pawlitzki M, Meuth SG, Boege F, Ruhrländer J. Chronic Fatigue and Dysautonomia following COVID-19 Vaccination Is Distinguished from Normal Vaccination Response by Altered Blood Markers. Vaccines (Basel). 2023 Oct 26;11(11):1642. doi: 10.3390/vaccines11111642. PMID: 38005974. https://www.mdpi.com/2076-393X/11/11/1642 (Full text)

Sequential activation of DNA viruses by the RNA virus SARS-CoV-2 in patients with long COVID syndrome

Abstract:

Background: Reactivation of Epstein-Barr virus (EBV) has been suggested to play role in long lasting multiorgan symptoms several months after the initial COVID-19 illness.
Purpose: The aim of our prospective study was to 1) to evaluate the reactivation of DNA viruses of EBV, Cytomegalovirus, Herpes simplex, Varicella zoster and Parvovirus-B19 by SARS-CoV-2 in patients with the diagnosis of long-COVID syndrome, 2) to investigate the effect of supposed virus reactivation on clinical conditions and long COVID syndromes.
Methods: Patients with long COVID syndrome were prospectively included into the Vienna PostCoV Registry between March 15th 2021 and September 30th 2021. – The time between COVID-19 infection and first clinical visit was 219±98 days (7±3 months). Clinical symptoms were documented and patients were divided into symptoms-oriented subgroups with dominantly respiratory, cardiovascular or neuropsychologic complaints. Qualitative and quantitative viral IgG and IgM titer of the selected DNA viruses of n=105 patients were compared with age and sex-matched healthy (non-infected, non-vaccinated, n=105) controls, who had neither spike- nor nucleocapsid antibodies, nor clinical history of COVID-19 disease.
Results: Long Covid patients had significantly higher cumulative number of IgM positivity of the DNA viruses (18.1% vs 6.7%, p=0.02), and significantly elevated quantitative EBV IgG (420±296 vs 339±282 mg/dL, p=0.033) and Parvo-B19 IgM (0.28±0.29 vs 0.03±0.12 mg/dL, p<0.001) titer as compared to healthy controls. Significantly more patients with long COVID symptoms had an EBV IgG titer above the detection limit as compared with healthy controls (40% vs 28%, p=0.018), suggesting EBV virus reactivation and chronic EBV infection. EBV IgG titer was significantly higher in patients with dominant respiratory symptoms, while elevated Parvo-B19 IgM titer was observed in patients with dominant cardiovascular complaints. In patients with long-COVID syndrome the quantitative EBV IgG titer increased with the time between infection and blood sampling (logarithmic correlation, p=0.011), suggesting the subclinical continuous EBV activation by the SARS-CoV2 RNA virus, while the quantitative Parvo-B19 IgM titer decreased linearly during the observation period
Conclusions: In this study of patients with long-COVID syndrome, SARS-CoV-2 infection apparently activated certain types of DNA viruses (EBV, and Parvo-B19), as demonstrated by the significantly higher incidence of cumulative IgM positivity, and elevated EBV IgG and parvovirus-B19 IgM titers, in long-COVID patients compared to healthy controls.
Source: M Gyongyosi, E Hasimbegovic, D Lukovic, K Zlabinger, A Spannbauer, E Samaha, J Bergler-Klein, C Hengstenberg, P Mucher, H Haslacher, M Breuer, R Strassl, M Riesenhuber, C Nitsche, T A Zelniker, Sequential activation of DNA viruses by the RNA virus SARS-CoV-2 in patients with long COVID syndrome, European Heart Journal, Volume 44, Issue Supplement_2, November 2023, ehad655.1823, https://doi.org/10.1093/eurheartj/ehad655.1823 https://academic.oup.com/eurheartj/article/44/Supplement_2/ehad655.1823/7393979 (Full text available as PDF file)

Risk Factors for Long COVID in Older Adults

Abstract:

As time has passed following the COVID-19 pandemic, individuals infected with SARS-CoV-2 have gradually exhibited a variety of symptoms associated with long COVID in the postacute phase of infection. Simultaneously, in many countries worldwide, the process of population aging has been accelerating. Within this context, the elderly population has not only become susceptible and high-risk during the acute phase of COVID-19 but also has considerable risks when confronting long COVID.
Elderly individuals possess specific immunological backgrounds, and during the process of aging, their immune systems can enter a state known as “immunosenescence”. This further exacerbates “inflammaging” and the development of various comorbidities in elderly individuals, rendering them more susceptible to long COVID. Additionally, long COVID can inflict both physical and mental harm upon elderly people, thereby reducing their overall quality of life. Consequently, the impact of long COVID on elderly people should not be underestimated.
This review seeks to summarize the infection characteristics and intrinsic factors of older adults during the COVID-19 pandemic, with a focus on the physical and mental impact of long COVID. Additionally, it aims to explore potential strategies to mitigate the risk of long COVID or other emerging infectious diseases among older adults in the future.
Source: Hu Y, Liu Y, Zheng H, Liu L. Risk Factors for Long COVID in Older Adults. Biomedicines. 2023; 11(11):3002. https://doi.org/10.3390/biomedicines11113002 https://www.mdpi.com/2227-9059/11/11/3002 (Full text)

Pharmacological evaluation of vitamin D in COVID-19 and long COVID-19: recent studies confirm clinical validation and highlight metformin to improve VDR sensitivity and efficacy

Abstract:

Nearly four years after its first appearance, and having gone from pandemic to endemic, the SARS-CoV-2 remains out of control globally. The purpose of this study was to evaluate the clinical efficacy of vitamin D (VD) in COVID-19 and long COVID-19, explain the discrepancy in clinical outcomes and highlight the potential impact of metformin on VD efficacy in recent articles.

Articles from January 2022 to August 2023 were selected for this review. The objective of this study was achieved by reviewing, analyzing, and discussing articles demonstrating (1) the mechanism of action of VD (2) observational or randomized clinical trials (RCTs) that support or not the beneficial clinical effects of VD in COVID-19 or long COVID. (3) genetic and non-genetic reasons for the variation in the effects of VD.

Articles were collected from electronic databases such as PubMed, Scopus, MEDLINE, Google Scholar, Egyptian Knowledge Bank, Science Direct, and Cochrane Database of Systematic Reviews. Twenty three studies conducted in vitro or in animal models indicated that VD may act in COVID-19 through protecting the respiratory system by antimicrobial peptide cathelicidins, reducing lung inflammation, regulating innate and adaptive immune functions and up regulation of autophagy gene activity. Our review identified 58 clinical studies that met the criteria. The number of publications supporting a beneficial clinical activity of VD in treating COVID-19 was 49 (86%), including 12 meta-analyses. Although the total patients included in all articles was 14,071,273, patients included in publications supporting a beneficial role of VD in COVID-19 were 14,029,411 (99.7%).

Collectively, extensive observational studies indicated a decisive relationship between low VD levels and the severity of COVID-19 and mortality outcomes. Importantly, evidence from intervention studies has demonstrated the effectiveness of VD supplements in treating COVID-19. Furthermore, the results of 4 observational studies supported the beneficial role of VD in alleviating symptoms of long COVID-19 disease. However, eight RCTs and one meta-analysis of RCTs may contain low-grade evidence against a beneficial role of VD in COVID-19. Twenty-five articles have addressed the association between VDR and DBP genetic polymorphisms and treatment failure of VD in COVID-19.

Impaired VDR signaling may underlie the variability of VD effects as non-genetic mechanisms. Interestingly, in recent studies, metformin has a beneficial therapeutic role in COVID-19 and long COVID-19, possibly by improving AMPK signaling of the VDR and enhancing the efficacy of the VD. In conclusion, evidence has been significantly strengthened over the past 18 months, with several meta-analyses and RCTs reporting conclusive beneficial effects of VD supplementation against COVID-19 and highlighting metformin to improve VDR sensitivity and efficacy in treating COVID-19 and long COVID-19.

Source: Gomaa, A.A., Abdel-Wadood, Y.A., Thabet, R.H. et al. Pharmacological evaluation of vitamin D in COVID-19 and long COVID-19: recent studies confirm clinical validation and highlight metformin to improve VDR sensitivity and efficacy. Inflammopharmacol (2023). https://doi.org/10.1007/s10787-023-01383-x https://link.springer.com/article/10.1007/s10787-023-01383-x (Full text)

Determinants of the onset and prognosis of the post-COVID-19 condition: a 2-year prospective observational cohort study

Abstract:

Background: At least 5-10% of subjects surviving COVID-19 develop the post-COVID-19 condition (PCC) or “Long COVID”. The clinical presentation of PCC is heterogeneous, its pathogenesis is being deciphered, and objective, validated biomarkers are lacking. It is unknown if PCC is a single entity or a heterogeneous syndrome with overlapping pathophysiological basis. The large US RECOVER study identified four clusters of subjects with PCC according to their presenting symptoms. However, the long-term clinical implications of PCC remain unknown.

Methods: We conducted a 2-year prospective cohort study of subjects surviving COVID-19, including individuals fulfilling the WHO PCC definition and subjects with full clinical recovery. We systematically collected post-COVID-19 symptoms using prespecified questionnaires and performed additional diagnostic imaging tests when needed. Factors associated with PCC were identified and modelled using logistic regression. Unsupervised clustering analysis was used to group subjects with PCC according to their presenting symptoms. Factors associated with PCC recovery were modelled using a direct acyclic graph approach.

Findings: The study included 548 individuals, 341 with PCC, followed for a median of 23 months (IQR 16.5-23.5), and 207 subjects fully recovered. In the model with the best fit, subjects who were male and had tertiary studies were less likely to develop PCC, whereas a history of headache, or presence of tachycardia, fatigue, neurocognitive and neurosensitive complaints and dyspnea at COVID-19 diagnosis predicted the development of PCC. The cluster analysis revealed the presence of three symptom clusters with an additive number of symptoms. Only 26 subjects (7.6%) recovered from PCC during follow-up; almost all of them (n = 24) belonged to the less symptomatic cluster A, dominated mainly by fatigue. Recovery from PCC was more likely in subjects who were male, required ICU admission, or had cardiovascular comorbidities, hyporexia and/or smell/taste alterations during acute COVID-19. Subjects presenting with muscle pain, impaired attention, dyspnea, or tachycardia, conversely, were less likely to recover from PCC.

Interpretation: Preexisting medical and socioeconomic factors, as well as acute COVID-19 symptoms, are associated with the development of and recovery from the PCC. Recovery is extremely rare during the first 2 years, posing a major challenge to healthcare systems.

Source: Mateu L, Tebe C, Loste C, Santos JR, Lladós G, López C, España-Cueto S, Toledo R, Font M, Chamorro A, Muñoz-López F, Nevot M, Vallejo N, Teis A, Puig J, Fumaz CR, Muñoz-Moreno JA, Prats A, Estany-Quera C, Coll-Fernández R, Herrero C, Casares P, Garcia A, Clotet B, Paredes R, Massanella M. Determinants of the onset and prognosis of the post-COVID-19 condition: a 2-year prospective observational cohort study. Lancet Reg Health Eur. 2023 Sep 5;33:100724. doi: 10.1016/j.lanepe.2023.100724. PMID: 37954002; PMCID: PMC10636281. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10636281/ (Full text)

Role of Tau protein in long COVID and potential therapeutic targets

Abstract:

Introduction: Long COVID is an emerging public health burden and has been defined as a syndrome with common symptoms of fatigue, shortness of breath, cognitive dysfunction, and others impacting day-to-day life, fluctuating or relapsing over, occurring for at least two months in patients with a history of probable or confirmed SARS CoV-2 infection; usually three months from the onset of illness and cannot be explained by an alternate diagnosis. The actual prevalence of long-term COVID-19 is unknown, but it is believed that more than 17 million patients in Europe may have suffered from it during pandemic.

Pathophysiology: Currently, there is limited understanding of the pathophysiology of this syndrome, and multiple hypotheses have been proposed. Our literature review has shown studies reporting tau deposits in tissue samples of the brain from autopsies of COVID-19 patients compared to the control group, and the in-vitro human brain organoid model has shown aberrant phosphorylation of tau protein in response to SARS-CoV-2 infection. Tauopathies, a group of neurodegenerative disorders with the salient features of tau deposits, can manifest different symptoms based on the anatomical region of brain involvement and have been shown to affect the peripheral nervous system as well and explained even in rat model studies.

Long COVID has more than 203 symptoms, with predominant symptoms of fatigue, dyspnea, and cognitive dysfunction, which tauopathy-induced CNS and peripheral nervous system dysfunction can explain. There have been no studies up till now to reveal the pathophysiology of long COVID. Based on our literature review, aberrant tau phosphorylation is a promising hypothesis that can be explored in future studies.

Therapeutic approaches for tauopathies have multidimensional aspects, including targeting post-translational modifications, tau aggregation, and tau clearance through the autophagy process with the help of lysosomes, which can be potential targets for developing therapeutic interventions for the long COVID. In addition, future studies can attempt to find the tau proteins in CSF and use those as biomarkers for the long COVID.

Source: Marwaha B. Role of Tau protein in long COVID and potential therapeutic targets. Front Cell Infect Microbiol. 2023 Oct 25;13:1280600. doi: 10.3389/fcimb.2023.1280600. PMID: 37953801; PMCID: PMC10634420. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10634420/ (Full text)