Category: Overlapping Illnesses

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)

No Causal Effects Detected in COVID-19 and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Two Sample Mendelian Randomization Study

Abstract

New clinical observational studies suggest that Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a sequela of COVID-19 infection, but whether there is an exact causal relationship between COVID-19 and ME/CFS remains to be verified. To investigate whether infection with COVID-19 actually causes ME/CFS, this paper obtained pooled data from the Genome Wide Association Study (GWAS) and analyzed the relationship between COVID susceptibility, hospitalization and severity of COVID and ME/CFS, respectively, using two-sample Mendelian randomization (TSMR).
TSMR analysis was performed by inverse variance weighting (IVW), weighted median method, MR-Egger regression and weighted mode and simple mode methods, respectively, and then the causal relationship between COVID-19 and ME/CFS was further evaluated by odds ratio (OR). Eventually, we found that COVID-19 severity, hospitalization and susceptibility were all not significantly correlated with ME/CFS (OR:1.000,1.000,1.000; 95% CI:0.999–1.000, 0.999–1.001, 0.998–1.002; p = 0.333, 0.862, 0.998, respectively). We found the results to be reliable after sensitivity analysis.
These results suggested that SARS-CoV-2 infection may not significantly contribute to the elevated risk of developing CFS, and therefore ME/CFS may not be a sequela of COVID-19, but may simply present with symptoms similar to those of CFS after COVID-19 infection, and thus should be judged and differentiated by physicians when diagnosing and treating the disease in clinical practice.
Source: Xu W, Cao Y, Wu L. No Causal Effects Detected in COVID-19 and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Two Sample Mendelian Randomization Study. International Journal of Environmental Research and Public Health. 2023; 20(3):2437. https://doi.org/10.3390/ijerph20032437 https://www.mdpi.com/1660-4601/20/3/2437 (Full text)

Long COVID (PASC) Is Maintained by a Self-Sustaining Pro-Inflammatory TLR4/RAGE-Loop of S100A8/A9 > TLR4/RAGE Signalling, Inducing Chronic Expression of IL-1b, IL-6 and TNFa: Anti-Inflammatory Ezrin Peptides as Potential Therapy

Abstract:

Long COVID, also referred to as Post-Acute Sequelae of COVID (PASC), is probably triggered during SARS-CoV-2 infection and acute COVID-19 by SARS-CoV-2 Spike-protein binding and hyper-activating the cell-membrane expressed Receptor for Advance Glycation End-products (mRAGE) and Toll-Like Receptor 4 (TLR4). SARS-CoV-2 infects lung monocytes by Spike binding to mRAGE (not ACE2).
During acute COVID-19, high levels of IL-6 hyper-stimulate S100A8/A9 expression and secretion. Although no viral protein nor mRNA can be detected in half of long COVID (PASC) patients, there is a significant elevation of serum levels of IL-1b, IL-6, TNFa, and S100A8/A9. It appears that a pathological pro-inflammatory feedback loop (the TLR4/RAGE-loop) is established during acute COVID-19, which is maintained by S100A8/A9 > RAGE/TLR4 chronic inflammatory signalling, even after SARS-CoV-2 has been cleared from the body. During long COVID/PASC, Ca2+-binding protein S100A8/A9 chronically stimulates TLR4/RAGE-signalling to induce chronic expression of IL-1b, IL-6 and TNFa. Secreted IL-6 binds to its IL-6R receptor on the surface of other cells and signals via STAT3 and C/EBPb for more S100A8/A9 expression. Secreted IL-1b binds to its receptor IL-1R on other cells, and signals via NFkB for more mRAGE and TLR4 expression. New S100A8/A9 can bind and activate cell-surface mRAGE and TLR4 to stimulate expression of more IL-1b, IL-6 and TNFa.
This process establishes a pathogenic pro-inflammatory TLR4/RAGE-loop: IL-1b + IL-6 > IL-1R + IL-6R > TLR4/mRAGE + S100A8/A9 > IL-1b + IL-6, which generates multi-organ inflammation that persists in the blood vessels, the brain, the liver, the heart, the kidneys, the gut and the musculo-skeletal system, and is responsible for all the complex pathologies associated with long COVID/PASC. Chronic expression of IL-1, IL-6 and TNFa is critical for the maintenance of the TLR4/RAGE-loop and persistence of long COVID/PASC.
Ezrin peptides are inhibitors of IL-1, IL-6, IL-8 and TNFa expression, so are now being investigated as potential therapy for long COVID/PASC. There is preliminary anecdotal evidence of symptomatic relief (not confirmed yet by formal clinical trials) from a few long COVID/PASC patient volunteers, after treatment with ezrin peptide therapy.
Source: Holms RD. Long COVID (PASC) Is Maintained by a Self-Sustaining Pro-Inflammatory TLR4/RAGE-Loop of S100A8/A9 > TLR4/RAGE Signalling, Inducing Chronic Expression of IL-1b, IL-6 and TNFa: Anti-Inflammatory Ezrin Peptides as Potential Therapy. Immuno. 2022; 2(3):512-533. https://doi.org/10.3390/immuno2030033 https://www.mdpi.com/2673-5601/2/3/33 (Full text)

SARS-CoV-2 infection and persistence in the human body and brain at autopsy

Abstract:

Coronavirus disease 2019 (COVID-19) is known to cause multi-organ dysfunction1-3 during acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some patients experiencing prolonged symptoms, termed post-acute sequelae of SARS-CoV-2 (refs. 4,5). However, the burden of infection outside the respiratory tract and time to viral clearance are not well characterized, particularly in the brain3,6-14.

Here we carried out complete autopsies on 44 patients who died with COVID-19, with extensive sampling of the central nervous system in 11 of these patients, to map and quantify the distribution, replication and cell-type specificity of SARS-CoV-2 across the human body, including the brain, from acute infection to more than seven months following symptom onset.

We show that SARS-CoV-2 is widely distributed, predominantly among patients who died with severe COVID-19, and that virus replication is present in multiple respiratory and non-respiratory tissues, including the brain, early in infection. Further, we detected persistent SARS-CoV-2 RNA in multiple anatomic sites, including throughout the brain, as late as 230 days following symptom onset in one case. Despite extensive distribution of SARS-CoV-2 RNA throughout the body, we observed little evidence of inflammation or direct viral cytopathology outside the respiratory tract.

Our data indicate that in some patients SARS-CoV-2 can cause systemic infection and persist in the body for months.

Source: Stein SR, Ramelli SC, Grazioli A, Chung JY, Singh M, Yinda CK, Winkler CW, Sun J, Dickey JM, Ylaya K, Ko SH, Platt AP, Burbelo PD, Quezado M, Pittaluga S, Purcell M, Munster VJ, Belinky F, Ramos-Benitez MJ, Boritz EA, Lach IA, Herr DL, Rabin J, Saharia KK, Madathil RJ, Tabatabai A, Soherwardi S, McCurdy MT; NIH COVID-19 Autopsy Consortium; Peterson KE, Cohen JI, de Wit E, Vannella KM, Hewitt SM, Kleiner DE, Chertow DS. SARS-CoV-2 infection and persistence in the human body and brain at autopsy. Nature. 2022 Dec;612(7941):758-763. doi: 10.1038/s41586-022-05542-y. Epub 2022 Dec 14. PMID: 36517603; PMCID: PMC9749650. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9749650/ (Full text)

Persistent SARS-CoV-2 infection in patients seemingly recovered from COVID-19

Abstract:

SARS-CoV-2 infection is clinically heterogeneous, ranging from asymptomatic to deadly. A few patients with COVID-19 appear to recover from acute viral infection but nevertheless progress in their disease and eventually die, despite persistent negativity at molecular tests for SARS-CoV-2 RNA.

Here, we performed post-mortem analyses in 27 consecutive patients who had apparently recovered from COVID-19 but had progressively worsened in their clinical conditions despite repeated viral negativity in nasopharyngeal swabs or bronchioalveolar lavage for 11-300 consecutive days (average: 105.5 days). Three of these patients remained PCR-negative for over 9 months.

Post-mortem analysis revealed evidence of diffuse or focal interstitial pneumonia in 23/27 (81%) patients, accompanied by extensive fibrotic substitution in 13 cases (47%). Despite apparent virological remission, lung pathology was similar to that observed in acute COVID-19 individuals, including micro- and macro-vascular thrombosis (67% of cases), vasculitis (24%), squamous metaplasia of the respiratory epithelium (30%), frequent cytological abnormalities and syncytia (67%), and the presence of dysmorphic features in the bronchial cartilage (44%).

Consistent with molecular test negativity, SARS-CoV-2 antigens were not detected in the respiratory epithelium. In contrast, antibodies against both spike and nucleocapsid revealed the frequent (70%) infection of bronchial cartilage chondrocytes and para-bronchial gland epithelial cells. In a few patients (19%), we also detected positivity in vascular pericytes and endothelial cells. Quantitative RT-PCR amplification in tissue lysates confirmed the presence of viral RNA.

Together, these findings indicate that SARS-CoV-2 infection can persist significantly longer than suggested by standard PCR-negative tests, with specific infection of specific cell types in the lung. Whether these persistently infected cells also play a pathogenic role in long COVID remains to be addressed.

Source: Bussani R, Zentilin L, Correa R, Colliva A, Silvestri F, Zacchigna S, Collesi C, Giacca M. Persistent SARS-CoV-2 infection in patients seemingly recovered from COVID-19. J Pathol. 2023 Jan 18. doi: 10.1002/path.6035. Epub ahead of print. PMID: 36651103. https://onlinelibrary.wiley.com/doi/10.1002/path.6035 (Full text)

Long Covid and Neurodegenerative Disease

Abstract:

Brain fog with compromised ability to concentrate has been the most frequent Long Covid (LC) complaint. This is due to an increased TGF beta/IFN gamma with consequently increased bradykinin (BKN), especially in Caucasian females. Brain and lung blood vessels “leak.” This same ratio is increased in Alzheimer’s disease (AD), but decreased in Parkinson’s disease (PD), because CD4+ and CD8+ T cells are differentially affected by the invading associated viruses, e.g., SARS CoV2, HIV, ….

In Covid-19 CD147 receptors on immune cells are critical in generating the increased TGF beta/IFN gamma and those on endothelial cells, platelets, and erythrocytes are critical to the abnormal microvascular blood flow. ACE2 receptors on pneumocytes and enterocytes enable pulmonary and GI entry, initiating gut dysbiosis.

Epigenetics, methylation, magnesium, vitamin D, the B vitamins, and antioxidants suggest that these issues can be surmounted. Biochemical, physiologic, and epidemiologic data are analyzed to answer these questions. An LC model is presented and discussed in the context of the most recent research. Suggestions to avoid these and other worrisome concerns are included. Other topics discussed include estrogen, the gut microbiome, type 2 diabetes (T2D), and homocysteine.

Source: Chambers, P. Long Covid and Neurodegenerative Disease. Preprints 2023, 2023020027 (doi: 10.20944/preprints202302.0027.v1) https://www.preprints.org/manuscript/202302.0027/v1 (Full text available as PDF file)