Category: Overlapping Illnesses

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)

A Prospect to Ameliorate Affective Symptoms and to Enhance Cognition in Long COVID Using Auricular Transcutaneous Vagus Nerve Stimulation

Abstract:

Long COVID, the postviral disorder caused by COVID-19, is expected to become one of the leading causes of disability in Europe. The cognitive consequences of long COVID have been described as “brain fog” and characterized by anxiety and depression, and by cognitive deficits. Long COVID is assumed to be a complex condition arising from multiple causes, including persistent brainstem dysfunction and disrupted vagal signaling.

We recommend the potential application of auricular transcutaneous vagus nerve stimulation (atVNS) as an ADD-ON instrument to compensate for the cognitive decline and to ameliorate affective symptoms caused by long COVID. This technique enhances vagal signaling by directly activating the nuclei in the brainstem, which are hypoactive in long COVID to enhance mood and to promote attention, memory, and cognitive control-factors affected by long COVID.

Considering that atVNS is a non-pharmacological intervention, its ADD-ON to standard pharmaceutical agents will be useful for non-responders, making of this method a suitable tool. Given that atVNS can be employed as an ecological momentary intervention (EMI), we outline the translational advantages of atVNS in the context of accelerating the cognitive and affective recovery from long COVID.

Source: Colzato LS, Elmers J, Beste C, Hommel B. A Prospect to Ameliorate Affective Symptoms and to Enhance Cognition in Long COVID Using Auricular Transcutaneous Vagus Nerve Stimulation. J Clin Med. 2023 Feb 2;12(3):1198. doi: 10.3390/jcm12031198. PMID: 36769845. https://www.mdpi.com/2077-0383/12/3/1198 (Full text)

Post-COVID conditions and healthcare utilization among adults with and without disabilities-2021 Porter Novelli FallStyles survey

Abstract:

Background: Adults with disabilities are at increased risk for SARS-CoV-2 infection and severe disease; whether adults with disabilities are at an increased risk for ongoing symptoms after acute SARS-CoV-2 infection is unknown.

Objectives: To estimate the frequency and duration of long-term symptoms (>4 weeks) and health care utilization among adults with and without disabilities who self-report positive or negative SARS-CoV-2 test results.

Methods: Data from a nationwide survey of 4510 U.S. adults administered from September 24, 2021-October 7, 2021, were analyzed for 3251 (79%) participants who self-reported disability status, symptom(s), and SARS-CoV-2 test results (a positive test or only negative tests). Multivariable models were used to estimate the odds of having ≥1 COVID-19-like symptom(s) lasting >4 weeks by test result and disability status, weighted and adjusted for socio-demographics.

Results: Respondents who tested positive for SARS-CoV-2 had higher odds of reporting ≥1 long-term symptom (with disability: aOR = 4.50 [95% CI: 2.37, 8.54] and without disability: aOR = 9.88 [95% CI: 7.13, 13.71]) compared to respondents testing negative. Among respondents who tested positive, those with disabilities were not significantly more likely to experience long-term symptoms compared to respondents without disabilities (aOR = 1.65 [95% CI: 0.78, 3.50]). Health care utilization for reported symptoms was higher among respondents with disabilities who tested positive (40%) than among respondents without disabilities who tested positive (18%).

Conclusions: Ongoing symptoms among adults with and without disabilities who also test positive for SARS-CoV-2 are common; however, the frequency of health care utilization for ongoing symptoms is two-fold among adults with disabilities.

Source: Miller MJ, Feldstein LR, Holbrook J, Plumb ID, Accorsi EK, Zhang QC, Cheng Q, Ko JY, Wanga V, Konkle S, Dimitrov LV, Bertolli J, Saydah S. Post-COVID conditions and healthcare utilization among adults with and without disabilities-2021 Porter Novelli FallStyles survey. Disabil Health J. 2022 Dec 19:101436. doi: 10.1016/j.dhjo.2022.101436. Epub ahead of print. PMID: 36740547; PMCID: PMC9762038. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9762038/ (Full text)

Autonomic dysfunction and postural orthostatic tachycardia syndrome in post-acute COVID-19 syndrome

Abstract:

The post-acute sequelae of COVID-19 present major problems for many patients, their physicians and the health-care system. They are unrelated to the severity of the initial infection, are often highly symptomatic and can occur after vaccination. Many sequelae involve cardiovascular autonomic dysfunction, with postural orthostatic tachycardia syndrome in 30% of individuals. Prognosis is unknown, and treatment is still unsatisfactory.

Source: Fedorowski A, Sutton R. Autonomic dysfunction and postural orthostatic tachycardia syndrome in post-acute COVID-19 syndrome. Nat Rev Cardiol. 2023 Feb 2:1–2. doi: 10.1038/s41569-023-00842-w. Epub ahead of print. PMID: 36732397; PMCID: PMC9893964. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9893964/ (Full text)

Myopathy as a cause of Long COVID fatigue: Evidence from quantitative and single fiber EMG and muscle histopathology

Highlights:

• Myopathic changes in qEMG and/or increased jitter in sfEMG were seen in 63% of 84 patients with Long COVID neuromuscular symptoms.

• Low quality of life score correlated with higher mean jitter values in sfEMG but not with qEMG measures.

• Electron microscopy showed damage of terminal nerves and motor endplate.Abstract:

Objective: To describe neurophysiological abnormalities in Long COVID and correlate quantitative electromyography (qEMG) and single fiber EMG (sfEMG) results to clinical scores and histopathology.

Methods: 84 patients with non-improving musculoskeletal Long COVID symptoms were examined with qEMG and sfEMG. Muscle biopsies were taken in a subgroup.

Results: Mean motor unit potential (MUP) duration was decreased in ≥1 muscles in 52% of the patients. Mean jitter was increased in 17% of the patients in tibialis anterior and 25% in extensor digitorum communis. Increased jitter was seen with or without myopathic qEMG. Low quality of life score correlated with higher jitter values but not with qEMG measures. In addition to our previously published mitochondrial changes, inflammation, and capillary injury, we show now in muscle biopsies damage of terminal nerves and motor endplate with abundant basal lamina material. At the endplate, axons were present but no vesicle containing terminals. The post-synaptic cleft in areas appeared atrophic with short clefts and coarse crests.

Conclusions: Myopathic changes are common in Long COVID. sfEMG abnormality is less common but may correlate with clinical scores. sfEMG changes may be due to motor endplate pathology.

Significance: These findings may indicate a muscle pathophysiology behind fatigue in Long COVID.

Source: Jane Agergaard, Benjamin Yamin Ali Khan, Thomas Engell-Sørensen, Berit Schiøttz-Christensen, Lars Østergaard, Eva K. Hejbøl, Henrik D. Schrøder, Henning Andersen, Jakob Blicher, Thomas Holm Pedersen, Thomas Harbo, Hatice Tankisi,
Myopathy as a cause of Long COVID fatigue: Evidence from quantitative and single fiber EMG and muscle histopathology,
Clinical Neurophysiology, 2023, ISSN 1388-2457, https://doi.org/10.1016/j.clinph.2023.01.010.
https://www.sciencedirect.com/science/article/pii/S1388245723000196 (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)

Persistent short nighttime sleep duration is associated with a greater post-COVID risk in fully mRNA-vaccinated individuals

Abstract:

Short nighttime sleep duration impairs the immune response to virus vaccination, and long nighttime sleep duration is associated with poor health status. Thus, we hypothesized that short (<6 h) and long (>9 h) nighttime sleepers have a higher post-COVID risk than normal nighttime sleepers, despite two doses of mRNA vaccine (which has previously been linked to lower odds of long-lasting COVID-19 symptoms). Post-COVID was defined as experiencing at least one core COVID-19 symptom for at least three months (e.g., shortness of breath).

Multivariate logistic regression adjusting for age, sex, BMI, and other factors showed in 9717 respondents (age span 18-99) that two mRNA vaccinations lowered the risk of suffering from post-COVID by about 21% (p < 0.001). When restricting the analysis to double-vaccinated respondents (n = 5918), short and long sleepers exhibited a greater post-COVID risk than normal sleepers (adjusted OR [95%-CI], 1.56 [1.29, 1.88] and 1.87 [1.32, 2.66], respectively). Among respondents with persistent sleep duration patterns during the pandemic compared to before the pandemic, short but not long sleep duration was significantly associated with the post-COVID risk (adjusted OR [95%-CI], 1.59 [1.24, 2.03] and 1.18 [0.70, 1.97], respectively). No significant association between sleep duration and post-COVID symptoms was observed in those reporting positive SARS-CoV-2 test results (n = 538).

Our findings suggest that two mRNA vaccinations against SARS-CoV-2 are associated with a lower post-COVID risk. However, this protection may be less pronounced among those sleeping less than 6 h per night. Our findings warrant replication in cohorts with individuals with confirmed SARS-CoV-2 infection.

Source: Xue P, Merikanto I, Chung F, Morin CM, Espie C, Bjorvatn B, Cedernaes J, Landtblom AM, Penzel T, De Gennaro L, Holzinger B, Matsui K, Hrubos-Strøm H, Korman M, Leger D, Mota-Rolim S, Bolstad CJ, Nadorff M, Plazzi G, Reis C, Chan RNY, Wing YK, Yordanova J, Bjelajac AK, Inoue Y, Partinen M, Dauvilliers Y, Benedict C. Persistent short nighttime sleep duration is associated with a greater post-COVID risk in fully mRNA-vaccinated individuals. Transl Psychiatry. 2023 Feb 1;13(1):32. doi: 10.1038/s41398-023-02334-4. PMID: 36726008; PMCID: PMC9890416. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9890416/ (Full text)