Tag: long covid review

Potential molecular mechanisms of chronic fatigue in long haul COVID and other viral diseases

Abstract:

Historically, COVID-19 emerges as one of the most devastating diseases of humankind, which creates an unmanageable health crisis worldwide. Until now, this disease costs millions of lives and continues to paralyze human civilization’s economy and social growth, leaving an enduring damage that will take an exceptionally long time to repair.

While a majority of infected patients survive after mild to moderate reactions after two to six weeks, a growing population of patients suffers for months with severe and prolonged symptoms of fatigue, depression, and anxiety. These patients are no less than 10% of total COVID-19 infected individuals with distinctive chronic clinical symptomatology, collectively termed post-acute sequelae of COVID-19 (PASC) or more commonly long-haul COVID. Interestingly, Long-haul COVID and many debilitating viral diseases display a similar range of clinical symptoms of muscle fatigue, dizziness, depression, and chronic inflammation.

In our current hypothesis-driven review article, we attempt to discuss the molecular mechanism of muscle fatigue in long-haul COVID, and other viral diseases as caused by HHV6, Powassan, Epstein-Barr virus (EBV), and HIV. We also discuss the pathological resemblance of virus-triggered muscle fatigue with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Source: Gottschalk CG, Peterson D, Armstrong J, Knox K, Roy A. Potential molecular mechanisms of chronic fatigue in long haul COVID and other viral diseases. Infect Agent Cancer. 2023 Feb 7;18(1):7. doi: 10.1186/s13027-023-00485-z. PMID: 36750846; PMCID: PMC9902840. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9902840/ (Full text)

Biomarkers in long COVID-19: A systematic review

Abstract:

Purpose: Long COVID, also known as post-acute sequelae of COVID-19, refers to the constellation of long-term symptoms experienced by people suffering persistent symptoms for one or more months after SARS-CoV-2 infection. Blood biomarkers can be altered in long COVID patients; however, biomarkers associated with long COVID symptoms and their roles in disease progression remain undetermined. This study aims to systematically evaluate blood biomarkers that may act as indicators or therapeutic targets for long COVID.

Methods: A systematic literature review in PubMed, Embase, and CINAHL was performed on 18 August 2022. The search keywords long COVID-19 symptoms and biomarkers were used to filter out the eligible studies, which were then carefully evaluated.

Results: Identified from 28 studies and representing six biological classifications, 113 biomarkers were significantly associated with long COVID: (1) Cytokine/Chemokine (38, 33.6%); (2) Biochemical markers (24, 21.2%); (3) Vascular markers (20, 17.7%); (4) Neurological markers (6, 5.3%); (5) Acute phase protein (5, 4.4%); and (6) Others (20, 17.7%). Compared with healthy control or recovered patients without long COVID symptoms, 79 biomarkers were increased, 29 were decreased, and 5 required further determination in the long COVID patients. Of these, up-regulated Interleukin 6, C-reactive protein, and tumor necrosis factor alpha might serve as the potential diagnostic biomarkers for long COVID. Moreover, long COVID patients with neurological symptoms exhibited higher levels of neurofilament light chain and glial fibrillary acidic protein whereas those with pulmonary symptoms exhibited a higher level of transforming growth factor beta.

Conclusion: Long COVID patients present elevated inflammatory biomarkers after initial infection. Our study found significant associations between specific biomarkers and long COVID symptoms. Further investigations are warranted to identify a core set of blood biomarkers that can be used to diagnose and manage long COVID patients in clinical practice.

Source: Lai YJ, Liu SH, Manachevakul S, Lee TA, Kuo CT, Bello D. Biomarkers in long COVID-19: A systematic review. Front Med (Lausanne). 2023 Jan 20;10:1085988. doi: 10.3389/fmed.2023.1085988. PMID: 36744129; PMCID: PMC9895110. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9895110/ (Full text)

Post-acute sequelae of SARS-CoV-2 (PASC) syndrome presenting as postural orthostatic tachycardia syndrome (POTS)

Abstract:

The novel SARS-CoV-2 emerged in 2019, and the global COVID-19 pandemic continues into 2022. It has been known that a subset of patients develops chronic, debilitating symptoms after otherwise complete recovery from acute infection of COVID-19.

Multiple terms have been used to describe this constellation of symptoms, including long COVID, long-haul COVID, and post-acute sequelae of SARS-CoV-2 syndrome (PASC). PASC is broadly defined as a wide range of new, returning, or ongoing symptoms at least four weeks after infection. Those patients are often seen in emergency departments after acute COVID- 19 infection, but their symptoms are not adequately managed because the underlying pathophysiology of PASC is not well understood.

Among patients with PASC, postural orthostatic tachycardic syndrome (POTS) has been increasingly recognized. POTS is one of the most common forms of autonomic dysfunction and defined by a sustained orthostatic tachycardia during active standing or head-up tilt test in the absence of orthostatic hypotension or other cardiopulmonary diseases. Because POTS is a treatable condition, it is important to recognize POTS among PASC patients. Herein, we reviewed the current literature on POTS and dysautonomia in PASC in order to better understand the overlap and distinction between these pathologies.

Source: Diekman S, Chung T. Post-acute sequelae of SARS-CoV-2 (PASC) syndrome presenting as postural orthostatic tachycardia syndrome (POTS). Clin Exp Emerg Med. 2023 Jan 30. doi: 10.15441/ceem.22.409. Epub ahead of print. PMID: 36718484. https://pubmed.ncbi.nlm.nih.gov/36718484/ (Full text available as PDF file)

Systematic review with meta-analysis of active herpesvirus infections in patients with COVID-19: Old players on the new field

Abstract:

Objectives: Herpesviruses are ubiquitous and after primary infection they establish lifelong latency. The impairment of maintaining latency with short-term or long-term consequences could be triggered by other infection. Therefore, reactivation of herpesviruses in COVID-19 patients represents an emerging issue.

Design and methods: This study provided the first systematic review with meta-analysis of studies that evaluated active human herpesvirus (HHV) infection (defined as the presence of IgM antibodies or HHV-DNA) in COVID-19 patients and included 36 publications collected by searching through PubMed, SCOPUS, and Web of science until November 2022.

Results: The prevalence of active EBV, HHV6, HSV, CMV, HSV1, and VZV infection in COVID-19 population was 41% (95% CI =27%-57%),3% (95% CI=17%-54%),28% (95% CI=1%-85%),25% (95% CI=1%-63%),22% (95% CI=10%-35%),and 18% (95% CI=4%-34%),respectively. There was a 6 times higher chance for active EBV infection in patients with severe COVID-19 than in non-COVID-19 controls (OR=6.45, 95% CI=1.09-38.13, p=0.040), although there was no difference in the prevalence of all evaluated active herpesvirus infections between COVID-19 patients and non-COVID-19 controls.

Conclusions: Future research of herpesvirus and SARS-CoV-2 coinfections must be prioritized to define: who, when and how to be tested, as well as how to effectively treat HHVs reactivations in acute and long COVID-19 patients.

Source: Banko A, Miljanovic D, Cirkovic A. Systematic review with meta-analysis of active herpesvirus infections in patients with COVID-19: Old players on the new field. Int J Infect Dis. 2023 Jan 31:S1201-9712(23)00037-1. doi: 10.1016/j.ijid.2023.01.036. Epub ahead of print. PMID: 36736577; PMCID: PMC9889115. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9889115/ (Full text)

Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID

Abstract:

A novel syndrome called long-haul COVID or long COVID is increasingly recognized in a significant percentage of individuals within a few months after infection with SARS-CoV-2. This disorder is characterized by a wide range of persisting, returning or even new but related symptoms that involve different tissues and organs, including respiratory, cardiac, vascular, gastrointestinal, musculo-skeletal, neurological, endocrine and systemic.
Some overlapping symptomatologies exist between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Very much like with long ME/CFS, infections with herpes family viruses, immune dysregulation, and the persistence of inflammation have been reported as the most common pattern for the development of long COVID.
This review describes several factors and determinants of long COVID that have been proposed, elaborating mainly on viral persistence, reactivation of latent viruses such as Epstein–Barr virus and human herpesvirus 6 which are also associated with the pathology of ME/CFS, viral superantigen activation of the immune system, disturbance in the gut microbiome, and multiple tissue damage and autoimmunity.
Based on these factors, we propose diagnostic strategies such as the measurement of IgG and IgM antibodies against SARS-CoV-2, EBV, HHV-6, viral superantigens, gut microbiota, and biomarkers of autoimmunity to better understand and manage this multi-factorial disorder that continues to affect millions of people in the world.
Source: Vojdani A, Vojdani E, Saidara E, Maes M. Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID. Viruses. 2023; 15(2):400. https://doi.org/10.3390/v15020400 https://www.mdpi.com/1999-4915/15/2/400 (Full text)

The direct correlation between microbiota and SARS-CoV-2 infectious disease

Abstract:

The human microbiota is the good part of the human organism and is a collection of symbiotic microorganisms which aid in human physiological functions. Diseases that can be generated by an altered microbiota are continuously being studied, but it is quite evident how a damaged microbiota is involved in chronic inflammatory diseases, psychiatric diseases, and some bacterial or viral infections. However, the role of the microbiota in the host immune response to bacterial and viral infections is still not entirely understood.

Metabolites or components which are produced by the microbiota are useful in mediating microbiota-host interactions, thus influencing the host’s immune capacity. Recent evidence shows that the microbiota is evidently altered in patients with viral infections such as post-acute COVID-19 syndrome (PACS).

In this review, the associations between microbiota and COVID-19 infection are highlighted in terms of biological and clinical significance by emphasizing the mechanisms through which metabolites produced by the microbiota modulate immune responses to COVID-19 infection.

Source: Vitiello A, Ferrara F, Zovi A. The direct correlation between microbiota and SARS-CoV-2 infectious disease. Inflammopharmacology. 2023 Feb 1:1–8. doi: 10.1007/s10787-023-01145-9. Epub ahead of print. PMID: 36725821; PMCID: PMC9891758. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9891758/ (Full text)

Long COVID Syndrome and Cardiovascular Manifestations: A Systematic Review and Meta-Analysis

Abstract:

Background: Long COVID syndrome is a significant cause of morbidity in COVID-19 patients who remain symptomatic with varied clinical presentations beyond three weeks. Furthermore, the relevance of considering cardiovascular outcomes in post-COVID-19 syndrome is important in the current COVID-19 pandemic.
Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed for this systematic review and meta-analysis. Systematic searches were conducted from multiple databases without language restrictions until October 8, 2022, to find studies evaluating cardiovascular outcomes such as arrhythmias, myocardium and pericardium diseases, coronary vessel disease, and thromboembolic disorders in post-COVID cases. The pooled odds ratio (OR), and standard mean difference (SMD) with their corresponding 95% confidence intervals (CI) were computed to find the association.
Results: Altogether, seven studies with a total of 8,126,462 (cases: 1,321,305; controls: 6,805,157) participants were included in the meta-analysis. Pooled odds ratios of cardiovascular outcomes were significantly higher in post-COVID cases (OR > 1, p < 0.05) than in controls. However, the mortality (OR: 4.76, p = 0.13), and heart rate variability (SMD: −0.06, p = 0.91) between cases and controls were not statistically significant.
Conclusions: Significant cardiovascular sequelae in long COVID syndrome highlight the importance of careful cardiac monitoring of COVID-19 patients in the post-COVID phase to address cardiovascular complications as soon as possible; larger-scale prospective studies are required for accurate estimation.
Source: Shrestha AB, Mehta A, Pokharel P, Mishra A, Adhikari L, Shrestha S, Yadav RS, Khanal S, Sah R, Nowrouzi-Kia B, Padhi BK, Chattu VK. Long COVID Syndrome and Cardiovascular Manifestations: A Systematic Review and Meta-Analysis. Diagnostics. 2023; 13(3):491. https://doi.org/10.3390/diagnostics13030491 https://www.mdpi.com/2075-4418/13/3/491 (Full text)

Functional Neurological Disorder in people with Long-Covid: A Systematic Review

Abstract:

Background: Acute health events, including infections, can trigger the onset of functional neurological disorder (FND). We hypothesised that a proportion of people with long-COVID might be experiencing functional symptoms.

Methods: We performed a systematic review of studies containing original data on long-COVID. We reviewed the frequency and characteristics of neurological symptoms, looking for positive evidence suggesting an underlying functional disorder, and the hypothesised causes of long-COVID.

Results: We included 102 studies in our narrative synthesis. The most consistently reported neurological symptoms were cognitive difficulties, headaches, pain, dizziness, fatigue, sleep-related symptoms, and ageusia/anosmia. Overall, we found no evidence that any authors had systematically looked for positive features of FND. An exception were three studies describing temporal inconsistency. In general, the neurological symptoms were insufficiently characterised in order to support or refute a diagnosis of FND. Moreover, only 13 studies specifically focussed on long-COVID after mild infection, where the impact of confounders from the general effects of severe illness would be mitigated. Only one study hypothesised that some people with long-COVID might have a functional disorder, and another 8 studies a chronic fatigue syndrome-like response.

Discussion: Neurological symptoms are prevalent in long-COVID, but poorly characterised. We are struck by the similarities between some manifestations of long-COVID and functional disorders triggered by acute illnesses. Unfortunately, the current literature is plagued by confounders, including the mixing of patients with initial mild infection with those with severe acute medical complications. The hypothesis that long-COVID might in part correspond to a functional disorder remains untested.

Source: Teodoro T, Chen J, Gelauff J, Edwards MJ. Functional Neurological Disorder in people with Long-Covid: A Systematic Review. Eur J Neurol. 2023 Jan 31. doi: 10.1111/ene.15721. Epub ahead of print. PMID: 36719069. https://onlinelibrary.wiley.com/doi/10.1111/ene.15721 (Full text available as PDF file)

Inflammatory and vascular biomarkers in post-COVID-19 syndrome: A systematic review and meta-analysis of over 20 biomarkers

Abstract:

Severe acute respiratory syndrome coronavirus 2 may inflict a post-viral condition known as post-COVID-19 syndrome (PCS) or long-COVID. Studies measuring levels of inflammatory and vascular biomarkers in blood, serum, or plasma of COVID-19 survivors with PCS versus non-PCS controls have produced mixed findings. Our review sought to meta-analyse those studies. A systematic literature search was performed across five databases until 25 June 2022, with an updated search on 1 November 2022.

Data analyses were performed with Review Manager and R Studio statistical software. Twenty-four biomarkers from 23 studies were meta-analysed. Higher levels of C-reactive protein (Standardized mean difference (SMD) = 0.20; 95% CI: 0.02-0.39), D-dimer (SMD = 0.27; 95% CI: 0.09-0.46), lactate dehydrogenase (SMD = 0.30; 95% CI: 0.05-0.54), and leukocytes (SMD = 0.34; 95% CI: 0.02-0.66) were found in COVID-19 survivors with PCS than in those without PCS. After sensitivity analyses, lymphocytes (SMD = 0.30; 95% CI: 0.12-0.48) and interleukin-6 (SMD = 0.30; 95% CI: 0.12-0.49) were also significantly higher in PCS than non-PCS cases. No significant differences were noted in the remaining biomarkers investigated (e.g., ferritin, platelets, troponin, and fibrinogen). Subgroup analyses suggested the biomarker changes were mainly driven by PCS cases diagnosed via manifestation of organ abnormalities rather than symptomatic persistence, as well as PCS cases with duration of <6 than ≥6 months.

In conclusion, our review pinpointed certain inflammatory and vascular biomarkers associated with PCS, which may shed light on potential new approaches to understanding, diagnosing, and treating PCS.

Source: Yong SJ, Halim A, Halim M, Liu S, Aljeldah M, Al Shammari BR, Alwarthan S, Alhajri M, Alawfi A, Alshengeti A, Khamis F, Alsalman J, Alshukairi AN, Abukhamis NA, Almaghrabi FS, Almuthree SA, Alsulaiman AM, Alshehail BM, Alfaraj AH, Alhawaj SA, Mohapatra RK, Rabaan AA. Inflammatory and vascular biomarkers in post-COVID-19 syndrome: A systematic review and meta-analysis of over 20 biomarkers. Rev Med Virol. 2023 Jan 27:e2424. doi: 10.1002/rmv.2424. Epub ahead of print. PMID: 36708022. https://pubmed.ncbi.nlm.nih.gov/36708022/ 

Mechanisms, Effects, and Management of Neurological Complications of Post-Acute Sequelae of COVID-19 (NC-PASC)

Abstract:

With a growing number of patients entering the recovery phase following infection with SARS-CoV-2, understanding the long-term neurological consequences of the disease is important to their care. The neurological complications of post-acute sequelae of SARS-CoV-2 infection (NC-PASC) represent a myriad of symptoms including headaches, brain fog, numbness/tingling, and other neurological symptoms that many people report long after their acute infection has resolved.
Emerging reports are being published concerning COVID-19 and its chronic effects, yet limited knowledge of disease mechanisms has challenged therapeutic efforts. To address these issues, we review broadly the literature spanning 2020–2022 concerning the proposed mechanisms underlying NC-PASC, outline the long-term neurological sequelae associated with COVID-19, and discuss potential clinical interventions.
Source: Ong IZ, Kolson DL, Schindler MK. Mechanisms, Effects, and Management of Neurological Complications of Post-Acute Sequelae of COVID-19 (NC-PASC). Biomedicines. 2023; 11(2):377. https://doi.org/10.3390/biomedicines11020377 https://www.mdpi.com/2227-9059/11/2/377