Tag: covid-19

Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC)

Abstract:

Exercise intolerance is a major manifestation of post-acute sequelae of severe acute respiratory syndrome coronavirus infection (PASC, or “long-COVID”). Exercise intolerance in PASC is associated with higher arterial blood lactate accumulation and lower fatty acid oxidation rates during graded exercise tests to volitional exertion, suggesting altered metabolism and mitochondrial dysfunction. It remains unclear whether the profound disturbances in metabolism that have been identified in plasma from patients suffering from acute coronavirus disease 2019 (COVID-19) are also present in PASC.

To bridge this gap, individuals with a history of previous acute COVID-19 infection that did not require hospitalization were enrolled at National Jewish Health (Denver, CO, USA) and were grouped into those that developed PASC (n = 29) and those that fully recovered (n = 16). Plasma samples from the two groups were analyzed via mass spectrometry-based untargeted metabolomics and compared against plasma metabolic profiles of healthy control individuals (n = 30). Observational demographic and clinical data were retrospectively abstracted from the medical record.

Compared to plasma of healthy controls or individuals who recovered from COVID-19, PASC plasma exhibited significantly higher free- and carnitine-conjugated mono-, poly-, and highly unsaturated fatty acids, accompanied by markedly lower levels of mono-, di- and tricarboxylates (pyruvate, lactate, citrate, succinate, and malate), polyamines (spermine) and taurine. Plasma from individuals who fully recovered from COVID-19 exhibited an intermediary metabolic phenotype, with milder disturbances in fatty acid metabolism and higher levels of spermine and taurine. Of note, depletion of tryptophan-a hallmark of disease severity in COVID-19-is not normalized in PASC patients, despite normalization of kynurenine levels-a tryptophan metabolite that predicts mortality in hospitalized COVID-19 patients.

In conclusion, PASC plasma metabolites are indicative of altered fatty acid metabolism and dysfunctional mitochondria-dependent lipid catabolism. These metabolic profiles obtained at rest are consistent with previously reported mitochondrial dysfunction during exercise, and may pave the way for therapeutic intervention focused on restoring mitochondrial fat-burning capacity.

Source: Guntur VP, Nemkov T, de Boer E, Mohning MP, Baraghoshi D, Cendali FI, San-Millán I, Petrache I, D’Alessandro A. Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC). Metabolites. 2022 Oct 26;12(11):1026. doi: 10.3390/metabo12111026. PMID: 36355108; PMCID: PMC9699059. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9699059/ (Full text)

Multi-kingdom gut microbiota analyses define COVID-19 severity and post-acute COVID-19 syndrome

Abstract:

Our knowledge of the role of the gut microbiome in acute coronavirus disease 2019 (COVID-19) and post-acute COVID-19 is rapidly increasing, whereas little is known regarding the contribution of multi-kingdom microbiota and host-microbial interactions to COVID-19 severity and consequences. Herein, we perform an integrated analysis using 296 fecal metagenomes, 79 fecal metabolomics, viral load in 1378 respiratory tract samples, and clinical features of 133 COVID-19 patients prospectively followed for up to 6 months.

Metagenomic-based clustering identifies two robust ecological clusters (hereafter referred to as Clusters 1 and 2), of which Cluster 1 is significantly associated with severe COVID-19 and the development of post-acute COVID-19 syndrome. Significant differences between clusters could be explained by both multi-kingdom ecological drivers (bacteria, fungi, and viruses) and host factors with a good predictive value and an area under the curve (AUC) of 0.98. A model combining host and microbial factors could predict the duration of respiratory viral shedding with 82.1% accuracy (error ± 3 days). These results highlight the potential utility of host phenotype and multi-kingdom microbiota profiling as a prognostic tool for patients with COVID-19.

Source: Liu Q, Su Q, Zhang F, Tun HM, Mak JWY, Lui GC, Ng SSS, Ching JYL, Li A, Lu W, Liu C, Cheung CP, Hui DSC, Chan PKS, Chan FKL, Ng SC. Multi-kingdom gut microbiota analyses define COVID-19 severity and post-acute COVID-19 syndrome. Nat Commun. 2022 Nov 10;13(1):6806. doi: 10.1038/s41467-022-34535-8. PMID: 36357381; PMCID: PMC9648868. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9648868/ (Full text)

COVID-19 disease severity to predict persistent symptoms: a systematic review and meta-analysis

Abstract:

Background: It is unclear, whether the initial disease severity may help to predict which COVID-19 patients at risk of developing persistent symptoms.

Aim: The aim of this study was to examine whether the initial disease severity affects the risk of persistent symptoms in post-acute COVID-19 syndrome and long COVID.

Methods: A systematic search was conducted using PUBMED, Google Scholar, EMBASE, and ProQuest databases to identify eligible articles published after January 2020 up to and including 30 August 2021. Pooled odds ratio (OR) and confidence intervals (CIs) were calculated using random effects meta-analysis.

Findings: After searching a total of 7733 articles, 20 relevant observational studies with a total of 7840 patients were selected for meta-analysis. The pooled OR for persistent dyspnea in COVID-19 survivors with a severe versus nonsevere initial disease was 2.17 [95%CI 1.62 to 2.90], and it was 1.33 [95%CI 0.75 to 2.33] for persistent cough, 1.30 [95%CI 1.06 to 1.58] for persistent fatigue, 1.02 [95%CI 0.73 to 1.40] for persistent anosmia, 1.22 [95%CI 0.69 to 2.16] for persistent chest pain, and 1.30 [95%CI 0.93 to 1.81] for persistent palpitation.

Conclusions: Contrary to expectations, we did not observe an association between the initial COVID-19 disease severity and common persistent symptoms except for dyspnea and fatigue. In addition, it was found that being in the acute or prolonged post-COVID phase did not affect the risk of symptoms. Primary care providers should be alert to potential most prevalent persistent symptoms in all COVID-19 survivors, which are not limited to patients with critical-severe initial disease.

Source: Dirican E, Bal T. COVID-19 disease severity to predict persistent symptoms: a systematic review and meta-analysis. Prim Health Care Res Dev. 2022 Nov 10;23:e69. doi: 10.1017/S1463423622000585. PMID: 36352492.  https://www.cambridge.org/core/journals/primary-health-care-research-and-development/article/covid19-disease-severity-to-predict-persistent-symptoms-a-systematic-review-and-metaanalysis/479FC1E900E22673895FDAC1CF5C12B2 (Full text)

Role of neuroinflammation mediated potential alterations in adult neurogenesis as a factor for neuropsychiatric symptoms in Post-Acute COVID-19 syndrome-A narrative review

Abstract:

Persistence of symptoms beyond the initial 3 to 4 weeks after infection is defined as post-acute COVID-19 syndrome (PACS). A wide range of neuropsychiatric symptoms like anxiety, depression, post-traumatic stress disorder, sleep disorders and cognitive disturbances have been observed in PACS. The review was conducted based on PRISMA-S guidelines for literature search strategy for systematic reviews.

A cytokine storm in COVID-19 may cause a breach in the blood brain barrier leading to cytokine and SARS-CoV-2 entry into the brain. This triggers an immune response in the brain by activating microglia, astrocytes, and other immune cells leading to neuroinflammation. Various inflammatory biomarkers like inflammatory cytokines, chemokines, acute phase proteins and adhesion molecules have been implicated in psychiatric disorders and play a major role in the precipitation of neuropsychiatric symptoms. Impaired adult neurogenesis has been linked with a variety of disorders like depression, anxiety, cognitive decline, and dementia.

Persistence of neuroinflammation was observed in COVID-19 survivors 3 months after recovery. Chronic neuroinflammation alters adult neurogenesis with pro-inflammatory cytokines supressing anti-inflammatory cytokines and chemokines favouring adult neurogenesis. Based on the prevalence of neuropsychiatric symptoms/disorders in PACS, there is more possibility for a potential impairment in adult neurogenesis in COVID-19 survivors. This narrative review aims to discuss the various neuroinflammatory processes during PACS and its effect on adult neurogenesis.

Source: Saikarthik J, Saraswathi I, Alarifi A, Al-Atram AA, Mickeymaray S, Paramasivam A, Shaikh S, Jeraud M, Alothaim AS. Role of neuroinflammation mediated potential alterations in adult neurogenesis as a factor for neuropsychiatric symptoms in Post-Acute COVID-19 syndrome-A narrative review. PeerJ. 2022 Nov 4;10:e14227. doi: 10.7717/peerj.14227. PMID: 36353605; PMCID: PMC9639419. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9639419/ (Full text)

Characterization of autonomic symptom burden in long COVID: A global survey of 2,314 adults

Abstract:

Background: Autonomic dysfunction is a known complication of post-acute sequelae of SARS-CoV-2 (PASC)/long COVID, however prevalence and severity are unknown.

Objective: To assess the frequency, severity, and risk factors of autonomic dysfunction in PASC, and to determine whether severity of acute SARS-CoV-2 infection is associated with severity of autonomic dysfunction.

Design: Cross-sectional online survey of adults with PASC recruited through long COVID support groups between October 2020 and August 2021.

Participants: 2,413 adults ages 18-64 years with PASC including patients who had a confirmed positive test for COVID-19 (test-confirmed) and participants who were diagnosed with COVID-19 based on clinical symptoms alone.

Main measures: The main outcome measure was the Composite Autonomic Symptom 31 (COMPASS-31) total score, used to assess global autonomic dysfunction. Test-confirmed hospitalized vs. test-confirmed non-hospitalized participants were compared to determine if the severity of acute SARS-CoV-2 infection was associated with the severity autonomic dysfunction.

Key results: Sixty-six percent of PASC patients had a COMPASS-31 score >20, suggestive of moderate to severe autonomic dysfunction. COMPASS-31 scores did not differ between test-confirmed hospitalized and test-confirmed non-hospitalized participants [28.95 (15.62, 46.60) vs. 26.4 (13.75, 42.10); p = 0.06].

Conclusions: Evidence of moderate to severe autonomic dysfunction was seen in 66% of PASC patients in our study, independent of hospitalization status, suggesting that autonomic dysfunction is highly prevalent in the PASC population and independent of the severity of acute COVID-19 illness.

Source: Larsen NW, Stiles LE, Shaik R, Schneider L, Muppidi S, Tsui CT, Geng LN, Bonilla H, Miglis MG. Characterization of autonomic symptom burden in long COVID: A global survey of 2,314 adults. Front Neurol. 2022 Oct 19;13:1012668. doi: 10.3389/fneur.2022.1012668. PMID: 36353127; PMCID: PMC9639503. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9639503/ (Full text)

Lifestyle, course of COVID-19, and risk of Long-COVID in non-hospitalized patients

Abstract:

Introduction: The coronavirus disease (COVID) 2019 pandemic remains a great challenge for the healthcare system. The widely reported prolonged signs and symptoms resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (Long-COVID) require medical care. The aim of the study was to assess factors, including lifestyle variables, related to the course of COVID-19 infection and to assess their impact on prolonged symptoms in non-hospitalized patients with COVID-19.

Methods: A total of 1,847 (637 men and 1,210 women) non-hospitalized participants of the STOP-COVID registry of the PoLoCOV-Study who, following the COVID-19, underwent check-up examinations at the cardiology outpatient clinic were included in the analysis.

Results: The study participants (median age 51 [41-62] years) were evaluated at 13.4 (8.4-23.6) weeks following the diagnosis of COVID-19. Female sex (odds ratio [OR] 1.46 [95% CI 1.19-1.78]), body mass index (BMI; per 1 kg/m2: 1.02 [1.00-1.04]), hypertension (1.39 [1.07-1.81]), asthma (1.55 [1.06-2.27]), stress or overworking (1.54 [1.25-1.90]), and nightshift work (1.51 [1.06-2.14]) were independently related to the severity of symptoms during acute phase of the COVID-19 infection. The Long-COVID syndrome was independently related to the female sex (1.42 [1.13-1.79]), history of myocardial infarction (2.57 [1.04-6.32]), asthma (1.56 [1.01-2.41]), and severe course of the acute phase of the COVID-19 infection (2.27 [1.82-2.83]).

Conclusion: Female sex, BMI, asthma, hypertension, nightshifts, and stress or overworking are significantly related to the severity of the acute phase of the COVID-19 infection, while female sex, asthma, history of myocardial infarction, and the severity of symptoms in the acute phase of COVID-19 are the predictors of Long-COVID in non-hospitalized patients. We did not find an independent relation between Long-COVID and the studied lifestyle factors.

Source: Pływaczewska-Jakubowska M, Chudzik M, Babicki M, Kapusta J, Jankowski P. Lifestyle, course of COVID-19, and risk of Long-COVID in non-hospitalized patients. Front Med (Lausanne). 2022 Oct 24;9:1036556. doi: 10.3389/fmed.2022.1036556. PMID: 36353225; PMCID: PMC9637668. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9637668/ (Full text)

Central hypersomnia and chronic insomnia: expanding the spectrum of sleep disorders in long COVID syndrome – a prospective cohort study

Abstract:

Introduction: Long-onset COVID syndrome has been described in patients with COVID-19 infection with persistence of symptoms or development of sequelae beyond 4 weeks after the onset of acute symptoms, a medium- and long-term consequence of COVID-19. This syndrome can affect up to 32% of affected individuals, with symptoms of fatigue, dyspnea, chest pain, cognitive disorders, insomnia, and psychiatric disorders. The present study aimed to characterize and evaluate the prevalence of sleep symptoms in patients with long COVID syndrome.

Methodology: A total of 207 patients with post-COVID symptoms were evaluated through clinical evaluation with a neurologist and specific exams in the subgroup complaining of excessive sleepiness.

Results: Among 189 patients included in the long COVID sample, 48 (25.3%) had sleep-related symptoms. Insomnia was reported by 42 patients (22.2%), and excessive sleepiness (ES) was reported by 6 patients (3.17%). Four patients with ES were evaluated with polysomnography and test, multiple sleep latencies test, and actigraphic data. Two patients had a diagnosis of central hypersomnia, and one had narcolepsy. A history of steroid use was related to sleep complaints (insomnia and excessive sleepiness), whereas depression was related to excessive sleepiness. We observed a high prevalence of cognitive complaints in these patients.

Conclusion: Complaints related to sleep, such as insomnia and excessive sleepiness, seem to be part of the clinical post-acute syndrome (long COVID syndrome), composing part of its clinical spectrum, relating to some clinical data.

Source: Moura AEF, Oliveira DN, Torres DM, Tavares-Júnior JWL, Nóbrega PR, Braga-Neto P, Sobreira-Neto MA. Central hypersomnia and chronic insomnia: expanding the spectrum of sleep disorders in long COVID syndrome – a prospective cohort study. BMC Neurol. 2022 Nov 9;22(1):417. doi: 10.1186/s12883-022-02940-7. PMID: 36352367; PMCID: PMC9643986. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9643986/ (Full text)

Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study

Abstract:

Growing evidence links COVID-19 with acute and long-term neurological dysfunction. However, the pathophysiological mechanisms resulting in central nervous system involvement remain unclear, posing both diagnostic and therapeutic challenges. Here we show outcomes of a cross-sectional clinical study (NCT04472013) including clinical and imaging data and corresponding multidimensional characterization of immune mediators in the cerebrospinal fluid (CSF) and plasma of patients belonging to different Neuro-COVID severity classes.

The most prominent signs of severe Neuro-COVID are blood-brain barrier (BBB) impairment, elevated microglia activation markers and a polyclonal B cell response targeting self-antigens and non-self-antigens. COVID-19 patients show decreased regional brain volumes associating with specific CSF parameters, however, COVID-19 patients characterized by plasma cytokine storm are presenting with a non-inflammatory CSF profile. Post-acute COVID-19 syndrome strongly associates with a distinctive set of CSF and plasma mediators. Collectively, we identify several potentially actionable targets to prevent or intervene with the neurological consequences of SARS-CoV-2 infection.

Source: Etter MM, Martins TA, Kulsvehagen L, Pössnecker E, Duchemin W, Hogan S, Sanabria-Diaz G, Müller J, Chiappini A, Rychen J, Eberhard N, Guzman R, Mariani L, Melie-Garcia L, Keller E, Jelcic I, Pargger H, Siegemund M, Kuhle J, Oechtering J, Eich C, Tzankov A, Matter MS, Uzun S, Yaldizli Ö, Lieb JM, Psychogios MN, Leuzinger K, Hirsch HH, Granziera C, Pröbstel AK, Hutter G. Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study. Nat Commun. 2022 Nov 9;13(1):6777. doi: 10.1038/s41467-022-34068-0. PMID: 36351919; PMCID: PMC9645766.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9645766/ (Full text)

Post COVID and Apheresis – Where are we Standing?

Abstract:

A continual increase in cases of Long/Post COVID constitutes a medical and socioeconomic challenge to health systems around the globe. While the true extent of this problem cannot yet be fully evaluated, recent data suggest that up to 20% of people with confirmed SARS-CoV-2 suffer from clinically relevant symptoms of Long/Post COVID several weeks to months after the acute phase. The clinical presentation is highly variable with the main symptoms being chronic fatigue, dyspnea, and cognitive symptoms. Extracorporeal apheresis has been suggested to alleviate symptoms of Post/COVID. Thus, numerous patients are currently treated with apheresis.

However, at present there is no data from randomized controlled trials available to confirm the efficacy. Therefore, physicians rely on the experience of practitioners and centers performing this treatment. Here, we summarize clinical experience on extracorporeal apheresis in patients with Post/COVID from centers across Germany.

Source: Steenblock C, Walther R, Tselmin S, Jarzebska N, Voit-Bak K, Toepfner N, Siepmann T, Passauer J, Hugo C, Wintermann G, Julius U, Barbir M, Khan TZ, Puhan MA, Straube R, Hohenstein B, Bornstein SR, Rodionov RN. Post COVID and Apheresis – Where are we Standing? Horm Metab Res. 2022 Nov;54(11):715-720. doi: 10.1055/a-1945-9694. Epub 2022 Sep 16. PMID: 36113501. https://www.thieme-connect.de/products/ejournals/html/10.1055/a-1945-9694 (Full text)

Post-acute symptoms 3-15 months after COVID-19 among unvaccinated and vaccinated individuals with a breakthrough infection

Abstract:

Objectives: We aimed to describe post-acute sequelae of SARS-CoV-2 infection (PASC) related symptoms 3-15 months after a positive test in SARS-CoV-2 unvaccinated and vaccinated participants with a breakthrough infection.

Methods: Participants of the Norwegian COVID-19 Cohort, without a positive SARS-CoV-2 test, filled in a questionnaire asking about PASC-related symptoms between November 2020 and January 2021. About a year later, a second questionnaire (which also included the Everyday Memory Questionnaire 13 (EMQ-13)) was filled in by the same participants, most still without a positive SARS-CoV-2 test, but also by unvaccinated and vaccinated participants with a positive test 3-15 months before the questionnaire. Laboratory-confirmed SARS-CoV-2 status (positive or negative swab test determined by reverse transcriptase quantitative polymerase chain reaction) at the time of completing questionnaires was ascertained from the Mandatory Norwegian Surveillance System for Communicable Diseases.

Results: No differences were found in the self-reported PASC-symptoms dyspnea, fatigue, smell/taste changes or concentration problems, or the EMQ-13 score between unvaccinated and vaccinated participants 3-15 months after the positive test. Less memory problems were reported among vaccinated than unvaccinated participants.

Conclusions: SARS-CoV-2 vaccines offer minor protection against PASC-symptoms, although less memory problems were reported among the vaccinated than the unvaccinated participants.

Source: Brunvoll SH, Nygaard AB, Fagerland MW, Holland P, Ellingjord-Dale M, Dahl JA, Søraas A. Post-acute symptoms 3-15 months after COVID-19 among unvaccinated and vaccinated individuals with a breakthrough infection. Int J Infect Dis. 2022 Nov 11;126:10–3. doi: 10.1016/j.ijid.2022.11.009. Epub ahead of print. PMID: 36375693; PMCID: PMC9651990. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9651990/ (Full text)