Tag: 2023

Long-term high-dose immunoglobulin successfully treats Long COVID patients with pulmonary, neurologic, and cardiologic symptoms

Abstract:

Introduction: Long COVID is the overarching name for a wide variety of disorders that may follow the diagnosis of acute SARS-COVID-19 infection and persist for weeks to many months. Nearly every organ system may be affected.

Methods: We report nine patients suffering with Long COVID for 101 to 547 days. All exhibited significant perturbations of their immune systems, but only one was known to be immunodeficient prior to the studies directed at evaluating them for possible treatment. Neurological and cardiac symptoms were most common. Based on this data and other evidence suggesting autoimmune reactivity, we planned to treat them for 3 months with long-term high-dose immunoglobulin therapy. If there was evidence of benefit at 3 months, the regimen was continued.

Results: The patients’ ages ranged from 34 to 79 years—with five male and four female patients, respectively. All nine patients exhibited significant immune perturbations prior to treatment. One patient declined this treatment, and insurance support was not approved for two others. The other six have been treated, and all have had a significant to remarkable clinical benefit.

Conclusion: Long-term high-dose immunoglobulin therapy is an effective therapeutic option for treating patients with Long COVID.

Source: Thompson JS, Thornton AC, Ainger T and Garvy BA (2023) Long-term high-dose immunoglobulin successfully treats Long COVID patients with pulmonary, neurologic, and cardiologic symptoms. Front. Immunol. 13:1033651. doi: 10.3389/fimmu.2022.1033651 https://www.frontiersin.org/articles/10.3389/fimmu.2022.1033651/full (Full text)

Risks and burdens of incident dyslipidaemia in long COVID: a cohort study

Abstract:

Background: Non-clinical evidence and a few human studies with short follow-ups suggest increased risk of dyslipidaemia in the post-acute phase of COVID-19 (ie, >30 days after SARS-CoV-2 infection). However, detailed large-scale controlled studies with longer follow-ups and in-depth assessment of the risks and burdens of incident dyslipidaemia in the post-acute phase of COVID-19 are not yet available. We, therefore, aimed to examine the risks and 1-year burdens of incident dyslipidaemia in the post-acute phase of COVID-19 among people who survive the first 30 days of SARS-CoV-2 infection.

Methods: In this cohort study, we used the national health-care databases of the US Department of Veterans Affairs to build a cohort of 51 919 participants who had a positive COVID-19 test and survived the first 30 days of infection between March 1, 2020, and Jan 15, 2021; a non-infected contemporary control group (n=2 647 654) that enrolled patients between March 1, 2020, and Jan 15, 2021; and a historical control group (n=2 539 941) that enrolled patients between March 1, 2018, and Jan 15, 2019. Control groups had no evidence of SARS-CoV-2 infection, and participants in all three cohorts were free of dyslipidaemia before cohort enrolment. We then used inverse probability weighting using predefined and algorithmically-selected high dimensional variables to estimate the risks and 1-year burdens of incident dyslipidaemia, lipid-lowering medications use, and a composite of these outcomes. We reported two measures of risk: hazard ratios (HRs) and burden per 1000 people at 12 months. Additionally, we estimated the risks and burdens of incident dyslipidaemia outcomes in mutually exclusive groups based on the care setting of the acute infection (ie, participants who were non-hospitalised, hospitalised, or admitted to intensive care during the acute phase of SARS-CoV-2 infection).

Findings: In the post-acute phase of the SARS-CoV-2 infection, compared with the non-infected contemporary control group, those in the COVID-19 group had higher risks and burdens of incident dyslipidaemia, including total cholesterol greater than 200 mg/dL (hazard ratio [HR] 1·26, 95% CI 1·22-1·29; burden 22·46, 95% CI 19·14-25·87 per 1000 people at 1 year), triglycerides greater than 150 mg/dL (1·27, 1·23-1·31; 22·03, 18·85-25·30), LDL cholesterol greater than 130 mg/dL (1·24, 1·20-1·29; 18·00, 14·98-21·11), and HDL cholesterol lower than 40 mg/dL (1·20, 1·16-1·25; 15·58, 12·52-18·73). The risk and burden of a composite of these abnormal lipid laboratory outcomes were 1·24 (95% CI 1·21-1·27) and 39·19 (95% CI 34·71-43·73), respectively. There was also increased risk and burden of incident lipid-lowering medications use (HR 1·54, 95% CI 1·48-1·61; burden 25·50, 95% CI 22·61-28·50). A composite of any dyslipidaemia outcome (laboratory abnormality or lipid-lowering medications use) yielded an HR of 1·31 (95% CI 1·28-1·34) and a burden of 54·03 (95% CI 49·21-58·92). The risks and burdens of these post-acute outcomes increased in a graded fashion corresponding to the severity of the acute phase of COVID-19 infection (ie, whether patients were non-hospitalised, hospitalised, or admitted to intensive care). The results were consistent in analyses comparing the COVID-19 group to the non-infected historical control group.

Interpretation: Our findings suggest increased risks and 1-year burdens of incident dyslipidaemia and incident lipid-lowering medications use in the post-acute phase of COVID-19 infection. Post-acute care for those with COVID-19 should involve attention to dyslipidaemia as a potential post-acute sequela of SARS-CoV-2 infection.

Source: Xu E, Xie Y, Al-Aly Z. Risks and burdens of incident dyslipidaemia in long COVID: a cohort study. Lancet Diabetes Endocrinol. 2023 Feb;11(2):120-128. doi: 10.1016/S2213-8587(22)00355-2. Epub 2023 Jan 6. PMID: 36623520; PMCID: PMC9873268. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9873268/ (Full text)

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

The emotional well-being of Long COVID patients in relation to their symptoms, social support and stigmatization in social and health services: a qualitative study

Abstract:

Background: Long COVID patients have experienced a decline in their quality of life due to, in part but not wholly, its negative emotional impact. Some of the most prevalent mental health symptoms presented by long COVID patients are anxiety, depression, and sleep disorders. As such, the need has arisen to analyze the personal experiences of these patients to understand how they are managing their daily lives while dealing with the condition. The objective of this study is to increase understanding about the emotional well-being of people diagnosed with long COVID.

Methods: A qualitative design was created and carried out using 35 patients, with 17 participants being interviewed individually and 18 of them taking part in two focus groups. The participating patients were recruited in November and December 2021 from Primary Health Care (PHC) centers in the city of Zaragoza (Northern Spain) and from the Association of Long COVID Patients in Aragon. The study topics were emotional well-being, social support networks, and experience of discrimination. All an inductive thematic content analyses were performed iteratively using NVivo software.

Results: The Long COVID patients identified low levels of self-perceived well-being due to their persistent symptoms, as well as limitations in their daily lives that had been persistent for many months. Suicidal thoughts were also mentioned by several patients. They referred to anguish and anxiety about the future as well as a fear of reinfection or relapse and returning to work. Many of the participants reported that they have sought the help of a mental health professional. Most participants identified discriminatory situations in health care.

Conclusions: It is necessary to continue researching the impact that Long COVID has had on mental health, as well as to provide Primary Health Care professionals with evidence that can guide the emotional treatment of these patients.

Source: Samper-Pardo M, Oliván-Blázquez B, Magallón-Botaya R, Méndez-López F, Bartolomé-Moreno C, León-Herrera S. The emotional well-being of Long COVID patients in relation to their symptoms, social support and stigmatization in social and health services: a qualitative study. BMC Psychiatry. 2023 Jan 25;23(1):68. doi: 10.1186/s12888-022-04497-8. PMID: 36698111; PMCID: PMC9875186. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9875186/ (Full text)

Panax ginseng improves physical recovery and energy utilization on chronic fatigue in rats through the PI3K/AKT/mTOR signalling pathway

Abstract:

Context: Panax ginseng C. A. Meyer (Araliaceae) is a tonic herb used in ancient Asia.

Objective: This study investigated the antifatigue effect of P. ginseng on chronic fatigue rats.

Materials and methods: Sprague-Dawley rats were divided into control, model and EEP (ethanol extraction of P. ginseng roots) (50, 100 and 200 mg/kg) groups (n = 8). The rats were subcutaneously handled with loaded swimming once daily for 26 days, except for the control group. The animals were intragastrically treated with EEP from the 15th day. On day 30, serum, liver and muscles were collected, and the PI3K/Akt/mTOR signalling pathway was evaluated.

Results: The swimming times to exhaust of the rats with EEP were significantly longer than that without it. EEP spared the amount of muscle glycogen, hepatic glycogen and blood sugar under the chronic state. In addition, EEP significantly (p < 0.05) decreased serum triglycerides (1.24 ± 0.17, 1.29 ± 0.04 and 1.20 ± 0.21 vs. 1.58 ± 0.13 mmol/L) and total cholesterol (1.64 ± 0.36, 1.70 ± 0.15 and 1.41 ± 0.19 vs. 2.22 ± 0.19 mmol/L) compared to the model group. Regarding the regulation of energy, EEP had a positive impact on promoting ATPase activities and relative protein expression of the PI3K/Akt/mTOR pathway.

Conclusions: Our results suggested that EEP effectively relieved chronic fatigue, providing evidence that P. ginseng could be a potential dietary supplement to accelerate recovery from fatigue.

Source: Zhang G, Lu B, Wang E, Wang W, Li Z, Jiao L, Li H, Wu W. Panax ginseng improves physical recovery and energy utilization on chronic fatigue in rats through the PI3K/AKT/mTOR signalling pathway. Pharm Biol. 2023 Dec;61(1):316-323. doi: 10.1080/13880209.2023.2169719. PMID: 36695132; PMCID: PMC9879180. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9879180/ (Full text)

Investigating the Genetic and Immunological Aetiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

This thesis describes two investigations into the disease Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), specifically its genetic aetiology and immune system alterations.

The first study investigated the genetic basis of ME/CFS using Genome-wide Association Studies (GWAS) by attempting to replicate and extend results previously found using UK Biobank cohort data. GWAS attempt to identify associations between DNA variants and phenotypes. T his GWAS was novel, conducted on new phenotypes constructed by combining those in the most up-to-date UK Biobank data release. A new, previously unseen, genome-wide significant association was found on chromosome 6 for males with ME/CFS within the gene PDE10A. Further results were not genome-wide significant, but many were suggestive and hence independent replication may justify further research.

A previous analysis on the UK Biobank cohort had identified an indicative association in females between variants around the SLC25A15 gene at genome-wide significance. I adopted a hypothesis that the dietary protein intake of people with the CFS risk variants would be lower than those with the alternative alleles, due to potentially reduced production of mitochondrial ornithine transporter 1 (ORNT1). However, this association with dietary protein intake was not supported by UK Biobank data.

Additionally, I investigated associations between the human leukocyte antigen (HLA) alleles and the ME/CFS phenotype using UK Biobank data. Associations between alleles within the HLA-C and -DQB1 genes had previously been found in a cohort of Norwegian people with ME/CFS, and my goal was to seek replication of these results in a larger dataset. None of the associations found in the UK Biobank proved to be genome-wide significant.

In my second study I investigated the use of T-cell clonal diversity as a potential biomarker for ME/CFS. This project used cells from CureME Biobank samples in collaboration with Systems Biology Laboratory (SBL). I developed a data analysis pipeline to analyse T-cell receptor (TCR) genomic DNA data based on the best practices currently used in the fields of immunology and mathematical biology. This approach used a mathematical notion of entropy as a measure for the diversity of TCR repertoires, in this way combining all of the most commonly used metrics in mathematical biology. When combined, these measures form a profile for each repertoire, a set of which can be sorted using a machine learning algorithm to partition the repertoires into subgroups.

My hypothesis was that the T-cell clonal expansion of people with ME/CFS would be greater than for healthy controls, and comparable to disease (multiple sclerosis) controls. Although this method was able to effectively classify TCR chains using simulated data, results from experimentally-derived data did not support the hypothesis, with the most effective classifications for both CD4+ and CD8+ cells failing to pass corrections for multiple hypothesis significance testing.

Lay summary

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease that affects millions of people around the world. Very little is understood about the cause or progression of the disease, and there is no known cure. At present, there is also no reliable clinical test to determine whether a person has ME/CFS.

This thesis explores the potential for a genetic or immunological basis for ME/CFS, with the goal to eventually find a biomarker that could be used in diagnosis.

The first part of this thesis investigates whether genetic variants are more (or less) common among those with ME/CFS than in the general population. In particular, the region of the genome that encodes immune system proteins was of interest, as previous studies have shown associations between this region and the disease.

Using strict statistical thresholds, none of the previously found associations were replicated. However, one new association was found, with the gene PDE10A, which is implicated in central nervous system diseases, such as Parkinsons and Huntingtons disease. This association has never been seen before, and would require replication in a new cohort before its role in ME/CFS could be confirmed. However, it represents a promising avenue for new research.

The second part of this thesis investigates T-cells. These are highly specialised immune cells in the blood, each of which targets an antigen (foreign substance) such as from a virus. When a T-cell recognises this antigen, it clones itself repeatedly. This clonal expansion is measurable, and can serve as evidence of immune system activation.

My hypothesis was that this immune signature could be used to distinguish people with ME/CFS from healthy controls and others diagnosed with another disease.

I used a mathematical measure of diversity and a machine learning method to sort their immune profiles into groups. However, the pattern of immune activation was not sufficiently clear to provide consistent classification. Hence, the role of the immune system in ME/CFS is still unclear, and the utility of this method as a diagnostic biomarker is not proved.

Source: Joshua James Dibble. Investigating the Genetic and Immunological Aetiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. PhD Thesis [University of Edinburgh]  https://era.ed.ac.uk/bitstream/handle/1842/39763/DibbleJJ_2022.pdf?sequence=1&isAllowed=y (Full text)

Orthostatic Intolerance and Chronotropic Incompetence in Patients With Myalgic Encephalomyelitis or Chronic Fatigue Syndrome

Abstract:

Background: Orthostatic intolerance markedly affects the day-to-day activities of patients with myalgic encephalomyelitis (ME) or chronic fatigue syndrome. Chronotropic incompetence (CI), defined as an impaired chronotropic response or reduced increases in heart rate during exercise and resulting in lower exercise capacity, may also be observed during orthostasis in patients with ME.

Methods and Results: In this study, the recordings of 101 adult patients with ME (36 men, 65 women; mean [±SD] age 37±12 years) who underwent conventional active 10-min standing tests at least 3 times to determine the presence of CI were analyzed. Recordings were selected for 13 patients who experienced tests both with and without exhibiting postural orthostatic tachycardia syndrome (POTS; an increase in heart rate of ≥30 beats/min or an actual heart rate of ≥120 beats/min) while also both successfully completing and failing to complete 10-min standing on different occasions. Subjects in whom failure without POTS was observed in any test(s) while success was associated with POTS on other occasions were considered positive for CI during orthostasis. Of the 13 patients, 12 (92%) were CI positive, 5 (38%) of whom exclusively failed the tests without experiencing POTS.

Conclusions: Some patients with ME were CI positive during standing tests, suggesting impaired sympathetic activation. The presence of POTS appears to be essential for maintaining orthostasis in these patients.

Source: Kunihisa Miwa. Orthostatic Intolerance and Chronotropic Incompetence in Patients With Myalgic Encephalomyelitis or Chronic Fatigue Syndrome. Circulation Reports, Article ID CR-22-0114. https://www.jstage.jst.go.jp/article/circrep/advpub/0/advpub_CR-22-0114/_html/-char/en (Full text)

What interventions or best practice are there to support people with Long COVID, or similar post-viral conditions or conditions characterised by fatigue, to return to normal activities: a rapid review

Abstract:

Previous research has categorised symptoms of COVID-19 / Long COVID into 12 thematic areas including: fever, myalgia, fatigue, impaired cognitive function, and that COVID-19 survivors had reduced levels of physical function, activities of daily living, and health-related quality of life.

Our aim was to review the evidence for interventions or best practice to support people with Long COVID, or similar post-viral conditions characterised by fatigue, to return to normal activities.

Evidence was included from guidelines, systematic reviews (SR), and primary studies. The primary studies focussed on Long COVID (LC) indicated that there should be a needs-based focus to care for those with LC.

Consideration should be given to individuals living with LC in the same way as people with disabilities are accommodated in terms of workplace adjustment.

Two SRs indicated that non-pharmaceutical interventions (NPIs) for patients with LC or chronic fatigue syndrome could help improve function for activities of daily life. However, the third, most recent SR, concluded that there is a lack of robust evidence for NPIs.

LC fatigue management methods may be beneficial under certain conditions. One SR reported work capability as an outcome however they did not find any studies which evaluated the impact of interventions on return to work/ normal life.

One primary study, on individuals with CFS, described a written self-management programme. Following this intervention there was an 18% increase in the number of patients in employment.

Policy and practice implications: Long COVID is still being established as a post-viral condition with many symptoms. Patient-centred treatment options such as occupational therapy, self-management therapy and talking therapy may be considered in the same way as for other debilitating conditions. Return-to-work accommodations are needed for all workers unable to return to full-time employment.

Due to the nature of the studies included, there was little reported evidence of effectiveness of getting individuals back into their normal activities.

Source: Llinos Haf Spencer, Annie Hendry, Abraham Makanjuola, Bethany F Anthony, Jacob Davies, Kalpa Pisavadia, Dyfrig Hughes, Deb Fitzsimmons, Clare Wilkinson, Rhiannon Tudor Edwards, Ruth Lewis, Alison Cooper, Adrian Edwards. What interventions or best practice are there to support people with Long COVID, or similar post-viral conditions or conditions characterised by fatigue, to return to normal activities: a rapid review. medRxiv 2023.01.24.23284947; doi: https://doi.org/10.1101/2023.01.24.23284947 (Full text)

Stress-Induced Transcriptomic Changes in Females with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Reveal Disrupted Immune Signatures

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex multi-organ illness characterized by unexplained debilitating fatigue and post-exertional malaise (PEM), which is defined as a worsening of symptoms following even minor physical or mental exertion. Our study aimed to evaluate transcriptomic changes in ME/CFS female patients undergoing an exercise challenge intended to precipitate PEM.
Our time points (baseline before exercise challenge, the point of maximal exertion, and after an exercise challenge) allowed for the exploration of the transcriptomic response to exercise and recovery in female patients with ME/CFS, as compared to healthy controls (HCs). Under maximal exertion, ME/CFS patients did not show significant changes in gene expression, while HCs demonstrated altered functional gene networks related to signaling and integral functions of their immune cells.
During the recovery period (commonly during onset of PEM), female ME/CFS patients showed dysregulated immune signaling pathways and dysfunctional cellular responses to stress. The unique functional pathways identified provide a foundation for future research efforts into the disease, as well as for potential targeted treatment options.
Source: Van Booven DJ, Gamer J, Joseph A, Perez M, Zarnowski O, Pandya M, Collado F, Klimas N, Oltra E, Nathanson L. Stress-Induced Transcriptomic Changes in Females with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Reveal Disrupted Immune Signatures. International Journal of Molecular Sciences. 2023; 24(3):2698. https://doi.org/10.3390/ijms24032698 https://www.mdpi.com/1422-0067/24/3/2698 (Full text)

Chronic viral coinfections differentially affect the likelihood of developing long COVID

Abstract:

BACKGROUND. The presence and reactivation of chronic viral infections, such as EBV, CMV, and HIV, have been proposed as potential contributors to long COVID (LC), but studies in well-characterized postacute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited.

METHODS. In a cohort of 280 adults with prior SARS-CoV-2 infection, we assessed the presence and types of LC symptoms and prior medical history (including COVID-19 history and HIV status) and performed serological testing for EBV and CMV using a commercial laboratory. We used covariate-adjusted binary logistic regression models to identify independent associations between variables and LC symptoms.

RESULTS. We observed that LC symptoms, such as fatigue and neurocognitive dysfunction, at a median of 4 months following initial diagnosis were independently associated with serological evidence suggesting recent EBV reactivation (early antigen–diffuse IgG positivity) or high nuclear antigen (EBNA) IgG levels but not with ongoing EBV viremia. Serological evidence suggesting recent EBV reactivation (early antigen–diffuse IgG positivity) was most strongly associated with fatigue (OR = 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR = 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR = 0.52).

CONCLUSION. Overall, these findings suggest differential effects of chronic viral coinfections on the likelihood of developing LC and association with distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted.

Source: Peluso MJ, Deveau TM, Munter SE, Ryder D, Buck A, Beck-Engeser G, Chan F, Lu S, Goldberg SA, Hoh R, Tai V, Torres L, Iyer NS, Deswal M, Ngo LH, Buitrago M, Rodriguez A, Chen JY, Yee BC, Chenna A, Winslow JW, Petropoulos CJ, Deitchman AN, Hellmuth J, Spinelli MA, Durstenfeld MS, Hsue PY, Kelly JD, Martin JN, Deeks SG, Hunt PW, Henrich TJ. Chronic viral coinfections differentially affect the likelihood of developing long COVID. J Clin Invest. 2023 Feb 1;133(3):e163669. doi: 10.1172/JCI163669. PMID: 36454631. https://www.jci.org/articles/view/163669 (Full text)