Tag: long Covid

Biological mechanisms underpinning the development of Long COVID

Abstract:

As COVID-19 evolves from a pandemic to an endemic disease, the already staggering number of people that have been or will be infected with SARS-COV-2 is only destined to increase, and the majority of humanity will be infected. It is well understood that COVID-19, like many other viral infections, leaves a significant fraction of the infected with prolonged consequences.

Continued high number of SARS-CoV-2 infections, viral evolution with escape from post-infection and vaccinal immunity, and reinfections heighten the potential impact of Long COVID. Hence, the impact of COVID-19 on human health will be seen for years to come until more effective vaccines and pharmaceutical treatments become available.

To that effect, it is imperative that the mechanisms underlying the clinical manifestations of Long COVID be elucidated. In this article, we provide an in-depth analysis of the evidence on several potential mechanisms of Long COVID and discuss their relevance to its pathogenesis.

Source: Perumal R, Shunmugam L, Naidoo K, Wilkins D, Garzino-Demo A, Brechot C, Vahlne A, Nikolich J. Biological mechanisms underpinning the development of Long COVID. iScience. 2023 May 18:106935. doi: 10.1016/j.isci.2023.106935. Epub ahead of print. PMCID: PMC10193768. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10193768/ https://www.cell.com/iscience/pdf/S2589-0042(23)01012-X.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS258900422301012X%3Fshowall%3Dtrue (Full text)

Cardiopulmonary testing in long COVID-19 versus non-COVID-19 patients with undifferentiated Dyspnea on exertion

Abstract:

Background: Dyspnea and fatigue are characteristics of long SARS-CoV-2 (COVID)-19. Cardiopulmonary exercise testing (CPET) can be used to better evaluate such patients.

Research question: How significantly and by what mechanisms is exercise capacity impaired in patients with long COVID who are coming to a specialized clinic for evaluation?

Study design and methods: We performed a cohort study using the Mayo Clinic exercise testing database. Subjects included consecutive long COVID patients without prior history of heart or lung disease sent from the Post-COVID Care Clinic for CPET. They were compared to a historical group of non-COVID patients with undifferentiated dyspnea also without known cardiac or pulmonary disease. Statistical comparisons were performed by t-test or Pearson’s chi2 test controlling for age, sex, and beta blocker use where appropriate.

Results: We found 77 patients with long COVID and 766 control patients. Long COVID patients were younger (47 ± 15 vs 50 ± 10 years, P < .01) and more likely female (70% vs 58%, P < .01). The most prominent difference on CPETs was lower percent predicted peak V̇O2 (73 ± 18 vs 85 ± 23%, p < .0001). Autonomic abnormalities (resting tachycardia, CNS changes, low systolic blood pressure) were seen during CPET more commonly in long COVID patients (34 vs 23%, P < .04), while mild pulmonary abnormalities (mild desaturation, limited breathing reserve, elevated V̇E/V̇CO2) during CPET were similar (19% in both groups) with only 1 long COVID patient showing severe impairment.

Interpretation: We identified severe exercise limitation among long COVID patients. Young women may be at higher risk for these complications. Though mild pulmonary and autonomic impairment were common in long COVID patients, marked limitations were uncommon. We hope our observations help to untangle the physiologic abnormalities responsible for the symptomatology of long COVID.

Source: Contreras AM, Newman DB, Cappelloni L, Niven AS, Mueller MR, Ganesh R, Squires RW, Bonikowske AR, Allison TG. Cardiopulmonary testing in long COVID-19 versus non-COVID-19 patients with undifferentiated Dyspnea on exertion. Prog Cardiovasc Dis. 2023 May 19:S0033-0620(23)00053-1. doi: 10.1016/j.pcad.2023.05.005. Epub ahead of print. PMID: 37211198; PMCID: PMC10198738. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10198738/ (Full text)

Prevalence of mental health problems among children with long COVID: A systematic review and meta-analysis

Abstract:

Introduction: The number of children with mental health problems has more than doubled since the COVID-19 pandemic. However, the effect of long Covid on children’s mental health is still debatable. Recognising long Covid as a risk factor for mental health problems in children will increase awareness and screening for mental health problems following COVID-19 infection, resulting in earlier intervention and lower morbidity. Therefore, this study aimed to determine the proportion of mental health problems post-COVID-19 infection in children and adolescents, and to compare them with the population with no previous COVID-19 infection.

Methodology: A systematic search was done in seven databases using pre-defined search terms. Cross-sectional, cohort and interventional studies reporting the proportion of mental health problems among children with long COVID in the English language from 2019 to May 2022 were included. Selection of papers, extraction of data and quality assessment were done independently by two reviewers. Studies with satisfactory quality were included in meta-analysis using R and Revman software programmes.

Results: The initial search retrieved 1848 studies. After screening, 13 studies were included in the quality assessments. Meta-analysis showed children who had previous COVID-19 infection had more than two times higher odds of having anxiety or depression, and 14% higher odds of having appetite problems, compared to children with no previous infection. The pooled prevalence of mental health problems among the population were as follows; anxiety: 9%(95% CI:1, 23), depression: 15%(95% CI:0.4, 47), concentration problems: 6%(95% CI: 3, 11), sleep problems: 9%(95% CI:5, 13), mood swings: 13% (95%CI:5, 23) and appetite loss: 5%(95% CI:1, 13). However, studies were heterogenous and lack data from low- and middle-income countries.

Conclusion: Anxiety, depression and appetite problems were significantly increased among post-COVID-19 infected children, compared to those without a previous infection, which may be attributed to long COVID. The findings underscore the importance of screening and early intervention of children post-COVID-19 infection at one month and between three to four months.

Source: Mat Hassan N, Salim HS, Amaran S, Yunus NI, Yusof NA, Daud N, et al. (2023) Prevalence of mental health problems among children with long COVID: A systematic review and meta-analysis. PLoS ONE 18(5): e0282538. https://doi.org/10.1371/journal.pone.0282538 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0282538 (Full text)

Laboratory Findings and Biomarkers in Long COVID: What Do We Know So Far? Insights Into Epidemiology, Pathogenesis, Therapeutic Perspectives and Challenges

Abstract:

Long COVID (LC) encompasses a constellation of long-term symptoms experienced by at least 10% of people after the initial SARS-CoV-2 infection, and so far has affected about 65 million people. The etiology of LC remains unclear; however, many pathophysiological pathways may be involved, including viral persistence; chronic, low grade inflammatory response; immune dysregulation and defective immune response; reactivation of latent viruses; autoimmunity; persistent endothelial dysfunction and coagulopathy; gut dysbiosis; hormonal dysregulation, mitochondrial dysfunction; and autonomic nervous system dysfunction.

There are no specific tests for the diagnosis of LC, and clinical features including laboratory findings and biomarkers may not specifically relate to LC. Therefore, it is of paramount importance to develop and validate biomarkers that can be employed for the prediction, diagnosis and prognosis of LC and its therapeutic response. Promising candidate biomarkers that are found in some patients are markers of systemic inflammation including acute phase proteins, cytokines and chemokines; biomarkers reflecting SARS-CoV-2 persistence, reactivation of herpesviruses and immune dysregulation; biomarkers of endotheliopathy, coagulation and fibrinolysis; microbiota alterations; diverse proteins and metabolites; hormonal and metabolic biomarkers; as well as cerebrospinal fluid biomarkers. At present, there are only two reviews summarizing relevant biomarkers; however, they do not cover the entire umbrella of current biomarkers or their link to etiopathogenetic mechanisms, and the diagnostic work-up in a comprehensive manner.

Herein, we aim to appraise and synopsize the available evidence on the typical laboratory manifestations and candidate biomarkers of LC, their classification based on main LC symptomatology in the frame of the epidemiological and pathogenetic aspects of the syndrome, and furthermore assess limitations and challenges as well as potential implications in candidate therapeutic interventions.

Source: Tsilingiris, D.; Vallianou, N.G.; Karampela, I.; Christodoulatos, G.S.; Papavasileiou, G.; Petropoulou, D.; Magkos, F.; Dalamaga, M. Laboratory Findings and Biomarkers in Long COVID: What Do We Know So Far? Insights Into Epidemiology, Pathogenesis, Therapeutic Perspectives and Challenges. Preprints.org 2023, 2023051487. https://doi.org/10.20944/preprints202305.1487.v1 (Full text available as PDF file)

Musculoskeletal involvement: COVID-19 and post COVID 19

Abstract:

The worldwide pandemic of coronavirus disease 2019 (COVID-19) was known to predominantly affect the lungs, but it was realized that COVID-19 had a large variety of clinical involvement. Cardiovascular, gastrointestinal, neurological, and musculoskeletal systems are involved by direct or indirect mechanisms with various manifestations.

The musculoskeletal involvement can manifest during COVID-19 infection, due to medications used for the treatment of COVID-19, and in the post/long COVID-19 syndrome. The major symptoms are fatigue, myalgia/arthralgia, back pain, low back pain, and chest pain. During the last two years, musculoskeletal involvement increased, but no clear consensus was obtained about the pathogenesis. However, there is valuable data that supports the hypothesis of angiotensinconverting enzyme 2, inflammation, hypoxia, and muscle catabolism. Additionally, medications that were used for treatment also have musculoskeletal adverse effects, such as corticosteroid-induced myopathy and osteoporosis. Therefore, while deciding the drugs, priorities and benefits should be taken into consideration.

Symptoms that begin three months from the onset of the COVID-19 infection, continue for at least two months, and cannot be explained by another diagnosis is accepted as post/long COVID-19 syndrome. Prior symptoms may persist and fluctuate, or new symptoms may manifest. In addition, there must be at least one symptom of infection. Most common musculoskeletal symptoms are myalgia, arthralgia, fatigue, back pain, muscle weakness, sarcopenia, impaired exercise capacity, and physical performance. In addition, the female sex, obesity, elderly patients, hospitalization, prolonged immobility, having mechanical ventilation, not having vaccination, and comorbid disorders can be accepted as clinical predictors for post/long COVID-19 syndrome.

Musculoskeletal pain is also a major problem and tends to be in chronic form. There is no consensus on the mechanism, but inflammation and angiotensin-converting enzyme 2 seem to play an important role. Localized and generalized pain may occur after COVID-19, and general pain is at least as common as localized pain. An accurate diagnosis allows physicians to initiate pain management and proper rehabilitation programs.

Source: Evcik D. Musculoskeletal involvement: COVID-19 and post COVID 19. Turk J Phys Med Rehabil. 2023 Feb 28;69(1):1-7. doi: 10.5606/tftrd.2023.12521. PMID: 37201006; PMCID: PMC10186015.

Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection

Key Points:

Question  What symptoms are differentially present in SARS-CoV-2–infected individuals 6 months or more after infection compared with uninfected individuals, and what symptom-based criteria can be used to identify postacute sequelae of SARS-CoV-2 infection (PASC) cases?

Findings  In this analysis of data from 9764 participants in the RECOVER adult cohort, a prospective longitudinal cohort study, 37 symptoms across multiple pathophysiological domains were identified as present more often in SARS-CoV-2–infected participants at 6 months or more after infection compared with uninfected participants. A preliminary rule for identifying PASC was derived based on a composite symptom score.

Meaning  A framework for identifying PASC cases based on symptoms is a first step to defining PASC as a new condition. These findings require iterative refinement that further incorporates clinical features to arrive at actionable definitions of PASC.

Abstract:

Importance  SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals.

Objective  To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections.

Design, Setting, and Participants  Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling.

Exposure  SARS-CoV-2 infection.

Main Outcomes and Measures  PASC and 44 participant-reported symptoms (with severity thresholds).

Results  A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months.

Conclusions and Relevance  A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

Source: Thaweethai T, Jolley SE, Karlson EW, et al. Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection. JAMA. Published online May 25, 2023. doi:10.1001/jama.2023.8823 https://jamanetwork.com/journals/jama/fullarticle/2805540 (Full text)

Autoantibodies to Selenoprotein P in Patients with Chronic Fatigue Syndrome Suggest Selenium Transport Impairment and Acquired Resistance to Thyroid Hormone

Abstract:

Chronic Fatigue Syndrome (CFS) presents with symptoms similar to hypothyroidism, including mental and physical fatigue, poor sleep, depression, and anxiety. However, the typical thyroid hormone (TH) profile of elevated thyrotropin (TSH) and low thyroxine (T4) is not observed. Recently, autoantibodies to the selenium transporter SELENOP (SELENOP-aAb) have been identified in Hashimoto’s thyroiditis and shown to impair selenium transport and selenoprotein expression. We hypothesized that SELENOP-aAb are prevalent in CFS and impair TH metabolism.

Selenium status in CFS (n=167) was compared to that of healthy controls (n=545). Two additional small groups were included, namely patients with fibromyalgia (FM; n=39), a disease often comorbid with CFS, and patients with post-COVID condition (n=24). The serum/plasma Se biomarkers total Se, glutathione peroxidase (GPx3) and SELENOP levels showed linear correlations without reaching saturation, indicative of Se deficiency. TSH and total T4 levels fitted within normal ranges, but relative total T3 (%TT3) was low, and relative rT3 (%rT3) was elevated in CFS. SELENOP-aAb prevalence was 9.6-15.6% in CFS versus 0.9-2.0% in controls, depending on cut-off for positivity.

An impairment of Se transport in SELENOP-aAb positive CFS patients is suggested by the lack of correlation between total Se and GPx3 activity. The same patients present with disturbed TH parameters, including low deiodinase (DIO) activity (SPINA-GD index) and particularly low urinary iodine as compared to controls (43.2 (16.0) vs. 89.0 (54.9) µg/L, P<0.001), indicating that SELENOP-aAb affect TH deiodination and iodine excretion.

We conclude that a considerable subset of CFS patients express SELENOP-aAb that disturb Se transport and cause low GPx3 and DIO activities. Hereby, TH deiodination decreases as an acquired condition that is not readily reflected by TSH or T4 in blood. This hypothesis opens new explanations and therapeutic options for SELENOP-aAb positive CFS and, perhaps, post-COVID condition patients, but requires additional clinical evidence from intervention trials.

Source: Sun, Qian and Oltra, Elisa and Dijck-Brouwer, D. A. Janneke and Chillon, Thilo Samson and Seemann, Petra and Asaad, Sabrina and Demircan, Kamil and Espejo-Oltra, José Andrés and Sánchez-Fito, Teresa and Martin-Martinez, Eva and Minich, Waldemar B. and Muskiet, Frits A. J. and Schomburg, Lutz, Autoantibodies to Selenoprotein P in Patients with Chronic Fatigue Syndrome Suggest Selenium Transport Impairment and Acquired Resistance to Thyroid Hormone. Available at SSRN: https://ssrn.com/abstract=4332223 or http://dx.doi.org/10.2139/ssrn.4332223 (Full text available as PDF file)

Viable SARS-CoV-2 Omicron sub-variants isolated from autopsy tissues

Introduction: Pulmonary and extrapulmonary manifestations have been described after infection with SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19). The virus is known to persist in multiple organs due to its tropism for several tissues. However, previous reports were unable to provide definitive information about whether the virus is viable and transmissible. It has been hypothesized that the persisting reservoirs of SARS-CoV-2 in tissues could be one of the multiple potentially overlapping causes of long COVID.

Methods: In the present study, we investigated autopsy materials obtained from 21 cadaveric donors with documented first infection or reinfection at the time of death. The cases studied included recipients of different formulations of COVID-19 vaccines. The aim was to find the presence of SARS-CoV-2 in the lungs, heart, liver, kidneys, and intestines. We used two technical approaches: the detection and quantification of viral genomic RNA using RT-qPCR, and virus infectivity using permissive in vitro Vero E6 culture.

Results: All tissues analyzed showed the presence of SARS-CoV-2 genomic RNA but at dissimilar levels ranging from 1.01 × 102 copies/mL to 1.14 × 108 copies/mL, even among those cases who had been COVID-19 vaccinated. Importantly, different amounts of replication-competent virus were detected in the culture media from the studied tissues. The highest viral load were measured in the lung (≈1.4 × 106 copies/mL) and heart (≈1.9 × 106 copies/mL) samples. Additionally, based on partial Spike gene sequences, SARS-CoV-2 characterization revealed the presence of multiple Omicron sub-variants exhibiting a high level of nucleotide and amino acid identity among them.

Discussion: These findings highlight that SARS-CoV-2 can spread to multiple tissue locations such as the lungs, heart, liver, kidneys, and intestines, both after primary infection and after reinfections with the Omicron variant, contributing to extending knowledge about the pathogenesis of acute infection and understanding the sequelae of clinical manifestations that are observed during post-acute COVID-19.

Source: Santiago Maffia-Bizzozero, Cintia Cevallos, Federico Remes Lenicov, Rosa Nicole Freiberger, Cinthya Alicia Marcela Lopez, Alex Guano Toaquiza, Franco Sviercz, Patricio Jarmoluk, Cristina Bustos, Adriana Claudia D’Addario, Jorge Quarleri, and M. Victoria Delpino. Viable SARS-CoV-2 Omicron sub-variants isolated from autopsy tissues. Front. Microbiol., 22 May 2023. https://www.frontiersin.org/articles/10.3389/fmicb.2023.1192832/full (Full text)

How Does Long-COVID Impact Prognosis and the Long-Term Sequelae?

Abstract:

Context: We reviewed what has been studied and published during the last 3 years about the consequences, mainly respiratory, cardiac, digestive, and neurological/psychiatric (organic and functional), in patients with COVID-19 of prolonged course.
Objective: To conduct a narrative review synthesizing current clinical evidence of abnormalities of signs, symptoms, and complementary studies in COVID-19 patients who presented a prolonged and complicated course.
Methods: A review of the literature focused on the involvement of the main organic functions mentioned, based almost exclusively on the systematic search of publications written in English available on PubMed/MEDLINE.
Results: Long-term respiratory, cardiac, digestive, and neurological/psychiatric dysfunction are present in a significant number of patients. Lung involvement is the most common; cardiovascular involvement may happen with or without symptoms or clinical abnormalities; gastrointestinal compromise includes the loss of appetite, nausea, gastroesophageal reflux, diarrhea, etc.; and neurological/psychiatric compromise can produce a wide variety of signs and symptoms, either organic or functional. Vaccination is not associated with the emergence of long-COVID, but it may happen in vaccinated people.
Conclusions: The severity of illness increases the risk of long-COVID. Pulmonary sequelae, cardiomyopathy, the detection of ribonucleic acid in the gastrointestinal tract, and headaches and cognitive impairment may become refractory in severely ill COVID-19 patients.
Source: Baroni C, Potito J, Perticone ME, Orausclio P, Luna CM. How Does Long-COVID Impact Prognosis and the Long-Term Sequelae? Viruses. 2023; 15(5):1173. https://doi.org/10.3390/v15051173 https://www.mdpi.com/1999-4915/15/5/1173 (Full text)

Long COVID: Plasma levels of neurofilament light chain in mild COVID-19 patients with neurocognitive symptoms

Abstract:

It is well known the potential of severe acute respiratory coronavirus type 2 (SARS-CoV-2) infection to induce post-acute sequelae, a condition called Long COVID. This syndrome includes several symptoms, but the central nervous system (CNS) main one is neurocognitive dysfunction. Recently it has been demonstrated the relevance of plasma levels of neurofilament light chain (pNfL), as a biomarker of early involvement of the CNS in COVID-19.

The aim of this study was to investigate the relationship between pNfL in patients with post-acute neurocognitive symptoms and the potential of NfL as a prognostic biomarker in these cases. A group of 63 long COVID patients ranging from 18 to 59 years-old were evaluated, submitted to a neurocognitive battery assessment, and subdivided in different groups, according to results. Plasma samples were collected during the long COVID assessment and used for measurement of pNfL with the Single molecule array (SIMOA) assays. Levels of pNfL were significantly higher in long COVID patients with neurocognitive symptoms when compared to HC (p = 0.0031).

Long COVID patients with cognitive impairment and fatigue symptoms presented higher pNfL levels when compared to long COVID patients without these symptoms, individually and combined (p = 0.0263, p = 0.0480, and 0.0142, respectively). Correlation analysis showed that levels of cognitive lost and exacerbation of fatigue in the neurocognitive evaluation had a significative correlation with higher pNfL levels (p = 0.0219 and 0.0255, respectively). Previous reports suggested that pNfL levels are related with higher risk of severity and predict lethality of COVID-19.

Our findings demonstrate that SARS-CoV-2 infection seems to have a long-term impact on the brain, even in patients who presented mild acute disease. NfL measurements might be useful to identify CNS involvement in long COVID associated with neurocognitive symptoms and to identify who will need continuous monitoring and treatment support.

Source: Gutman E, Salvio A, Fernandes R, et al. Long COVID: Plasma levels of neurofilament light chain in mild COVID-19 patients with neurocognitive symptoms. Research Square; 2023. DOI: 10.21203/rs.3.rs-2921879/v1. https://www.researchsquare.com/article/rs-2921879/v1 (Full text)